Fused Tricyclic Pyridazinone Compounds Useful to Treat Orthomyxovirus Infections

ABSTRACT

The invention provides compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     as further described herein, as well as pharmaceutical compositions comprising such compounds, and methods to use the compounds and pharmaceutical compositions for treatment of certain viral disorders, including influenza.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.16/328,616, filed 26 Feb. 2019, which application is a national stageapplication of PCT/IB2017/055137, filed 25 Aug. 2017, which claims thebenefit of and priority to U.S. Provisional Application No. 62/380,712,filed 29 Aug. 2016, the contents of each of which are incorporatedherein by reference.

FIELD OF THE INVENTION

The invention provides compounds that inhibit orthomyxovirusreplication, and are accordingly useful for treatment of viralinfections caused by orthomyxoviruses. The invention further providespharmaceutical compositions containing these compounds and methods ofusing these compounds to treat or prevent viral infections caused byorthomyxovirus.

BACKGROUND

Orthomyxoviruses have negative-sense single stranded RNA genomes, andreplicate in the nucleus of infected cells, as they lack the machineryto generate the cap structure to produce their own mRNA. Members of theOrthomyxovirus family have an RNA-dependent RNA polymerase withendonuclease activity that cleaves a section of the capped 5′-end ofcellular mRNA; the RNA polymerase then uses the cleavage product as aprimer for synthesis of viral mRNA. This process is known ascap-snatching. This endonuclease has been recognized as a promisingtarget for development of antivirals effective against orthomyxoviruses.ACS Med. Chem. Letters, 2014, vol. 5, 61-64. Inhibitors of thisendonuclease have been disclosed, for example, in WO2015/038660, U.S.Pat. No. 8,987,441, WO2010/147068, and U.S. patent applicationsUS2012/022251, US2013/0197219, US2014/256937, and US2015/0072982, whichreport that such inhibitors are useful to treat influenza infections inmammals.

The orthomyxovirus family includes influenza A, influenza B andinfluenza C, all of which can infect humans, as well as several othergenera of viruses that generally do not infect humans. Influenza A isthe most virulent of these pathogens in humans, often accounting for themajority of serious cases of influenza during a typical flu season. Itis estimated that influenza kills as many as 40,000 people per year inthe U.S., in spite of the widespread use of vaccines to reduce theincidence of influenza; thus there is a great need for antiviraltherapeutics effective to treat influenza, especially influenza A. Thepresent invention provides compounds that inhibit replication oforthomyxoviruses, including influenza A, influenza B and influenza C.Without being bound by theory, it is believed these compounds achievetheir antiviral effects by inhibiting the endonuclease function of theviral polymerase. Because this endonuclease is highly conserved acrossinfluenza A viruses (id.), the compounds are especially useful fortreatment of influenza A.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a compound of Formula (A):

as further described herein.

In another aspect, the invention provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, halo, CN, COOR*, —CONR*₂, or C₁-C₆ alkyl optionally substitutedwith one or two groups selected from —OR* and —NR*₂, C₁-C₄ haloalkyl;

-   -   R* is independently at each occurrence H or C₁-C₆ alkyl        optionally substituted with —OR or —NR₂;

Z¹ is N, and Z² is C(R)₂;

-   -   or Z¹ is CH, and Z² is NR, O, S, or CH₂;

Z³ is CH₂, Q, —CH₂—CH₂—, -Q-CH₂—, —CH₂-Q-, —CH₂-Q-CH₂— or —CH₂—CH₂—CH₂—;

Q is selected from —NR—, O, S, SO, and SO₂;

R² is selected from H, halo, CN, C₁₋₄ alkyl optionally substituted withup to three groups independently selected from halo, CN, C₁₋₄ alkyl,—OR, C₁₋₄ haloalkoxy, —NR₂, and C₁₋₄ haloalkyl, OR, and C₁-C₄ haloalkyl;

each R³ is a substituent optionally present on any carbon atom of thering containing Z² and Z³, and is independently selected from —OR, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, oxo, CN, —NR₂, and C₁₋₄ alkyl optionallysubstituted with up to three groups independently selected from halo,CN, C₁₋₄ alkyl, —OR, C₁₋₄ haloalkoxy, —NR₂, and C₁₋₄ haloalkyl;

n is 0-2;

Ar¹ and Ar² each independently represent phenyl or a 5-6 memberedheteroaryl ring containing 1-3 heteroatoms selected from N, O and S asring members, and are each independently substituted with up to threegroups selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, C₂₋₄alkyne, and CN;

-   -   and Ar¹ and Ar² are optionally linked together by a bridge of        the formula —C(R^(L))₂-L- to form a tricyclic group, wherein Ar¹        and Ar² are each optionally substituted by up to two groups        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkyne, and CN;

R is independently at each occurrence H or C₁-C₄ alkyl optionallysubstituted with up to three groups independently selected from halo,OH, oxo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ haloalkyl;

-   -   L is selected from S, S═O, SO₂, O, NR, C(R^(L))₂ and CF₂; and    -   and each R^(L) is independently H or C₁₋₂ alkyl;        as further described herein.        The invention includes these compounds, their pharmaceutically        acceptable salts, and compositions and combinations comprising        these compounds (including pharmaceutically acceptable salts),        and methods of using the same as further described herein.

The compounds of Formula (A) are inhibitors of the endonuclease functionof influenza viruses as shown by the data provided herein, and theyinhibit replication of influenza viruses. Accordingly, these compoundsare useful to treat or prevent orthomyxovirus infections in mammalssusceptible to such infections, and are particularly useful to treatinfluenza virus infections in humans. They are also useful to inhibitreplication of orthomyxoviruses, including influenza viruses, in cells.

In another aspect, the invention provides pharmaceutical compositionscomprising a compound of Formula (A) admixed with at least onepharmaceutically acceptable carrier or excipient, optionally admixedwith two or more pharmaceutically acceptable carriers or excipients. Thecompounds may be used as pharmaceutically acceptable salts.

In another aspect, the invention provides a method to treat a subjectinfected with influenza A, B or C, which comprises administering to asubject in need of such treatment an effective amount of a compound ofFormula (A) or any subgenus or species thereof as described herein, or apharmaceutical composition comprising such compound. The subject can bea mammal, and is preferably a human, although the compounds and methodsof the invention are suitable for treatment of other species thatcontract Influenza A, Influenza B, or influenza C, as well as otherorthomyxoviruses. The invention includes compounds of Formula (A) andthe subgenera of Formula (I) described herein, and all stereoisomers(including diastereoisomers and enantiomers) except where a specificisomer is expressly described, as well as tautomers and isotopicallyenriched versions thereof (including deuterium substitutions) as well aspharmaceutically acceptable salts of these compounds. Compounds of thepresent invention also comprise polymorphs of compounds of formula (A)(or subformulae thereof) and salts thereof.

DETAILED DESCRIPTION

The following definitions apply unless otherwise expressly provided:

As used herein, the term “halogen” or “halo” refers to fluorine,bromine, chlorine or iodine, in particular it typically refers tofluorine or chlorine when attached to an alkyl group, and furtherincludes bromine or iodine when on an aryl or heteroaryl group.

As used herein, unless otherwise specified, the term “heteroatom” refersto a nitrogen (N), oxygen (O) or sulfur (S) atom.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety having up to 10 carbon atoms. Unlessotherwise provided, alkyl refers to hydrocarbon moieties having 1 to 6carbon atoms. Representative examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl,n-octyl, n-nonyl, n-decyl and the like. A substituted alkyl is an alkylgroup containing one or more substituents in place of hydrogen, such asone, two, or three substituents, up to the number of hydrogens presenton the unsubstituted alkyl group. Suitable substituents for alkylgroups, if not otherwise specified, may be selected from halogen, CN,oxo, hydroxy, C₁₋₄alkoxy, substituted or unsubstituted C₃₋₆ cycloalkyl,substituted or unsubstituted phenyl, amino, (C₁₋₄ alkyl)amino,di(C₁₋₄alkyl)amino, C₁₋₄ alkylthio, C₁₋₄ alkylsulfonyl, —C(═O)—C₁₋₄alkyl, COOH, COO(C₁₋₄ alkyl), —O(C═O)—C₁₋₄ alkyl, —NHC(═O)C₁₋₄ alkyl and—NHC(═O)OC₁₋₄ alkyl groups, where substituents for the substitutedcycloalkyl or phenyl are up to three groups selected from Me, Et, —OMe,—OEt, CF₃, halo, CN, OH, and NH₂.

As used herein, the term “alkylene” refers to a divalent alkyl grouphaving 1 to 10 carbon atoms, and two open valences to attach to otherfeatures. Unless otherwise provided, alkylene refers to moieties having1 to 6 carbon atoms. Representative examples of alkylene include, butare not limited to, methylene, ethylene, n-propylene, iso-propylene,n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene,isopentylene, neopentylene, n-hexylene, 2,2-dimethylbutylene, and thelike. A substituted alkylene is an alkylene group containing one ormore, such as one, two or three substituents; unless otherwisespecified, suitable substituents for an alkylene group are selected fromthe substituents listed above for alkyl groups.

As used herein, the term “haloalkyl” refers to an alkyl as definedherein, which is substituted by one or more halo groups. The haloalkylcan be monohaloalkyl, dihaloalkyl, trihaloalkyl, or polyhaloalkylincluding perhaloalkyl. A monohaloalkyl can have one chloro or fluorowithin the alkyl group. Chloro and fluoro are commonly present assubstituents on alkyl or cycloalkyl groups; fluoro, chloro and bromo areoften present on aryl or heteroaryl groups. Dihaloalkyl andpolyhaloalkyl groups can have two or more of the same halo atoms or acombination of different halo groups on the alkyl. Typically thepolyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2halo groups. Non-limiting examples of haloalkyl include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. Aperhalo-alkyl refers to an alkyl having all hydrogen atoms replaced withhalo atoms, e.g., trifluoromethyl.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined above. Representative examples of alkoxy include, but are notlimited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy,pentyloxy, hexyloxy, and the like. Typically, alkoxy groups have 1-6carbons, more commonly 1-4 carbon atoms.

A “substituted alkoxy” is an alkoxy group containing one or more, suchas one, two or three substituents on the alkyl portion of the alkoxy.Unless otherwise specified, suitable substituents are selected from thesubstituents listed above for alkyl groups, except that hydroxyl andamino are not normally present on the carbon that is directly attachedto the oxygen of the substituted ‘alkyl-O’ group.

Similarly, each alkyl part of other groups like “alkylaminocarbonyl”,“alkoxyalkyl”, “alkoxycarbonyl”, “alkoxy-carbonylalkyl”,“alkylsulfonyl”, “alkylsulfoxyl”, “alkylamino”, “haloalkyl” shall havethe same meaning as described in the above-mentioned definition of“alkyl”. When used in this way, unless otherwise indicated, the alkylgroup is often a 1-4 carbon alkyl and is not further substituted bygroups other than the component named. When such alkyl groups aresubstituted, suitable substituents are those named above for alkylgroups unless, otherwise specified.

As used herein, the term “haloalkoxy” refers to haloalkyl-O—, whereinhaloalkyl is defined above. Representative examples of haloalkoxyinclude, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, trichloromethoxy, 2-chloroethoxy,2,2,2-trifluoroethoxy, 1,1,1,3,3,3-hexafluoro-2-propoxy, and the like.Typically, haloalkyl groups have 1-4 carbon atoms.

As used herein, the term “cycloalkyl” refers to saturated or unsaturatednon-aromatic monocyclic, bicyclic, tricyclic or spirocyclic hydrocarbongroups of 3-12 carbon atoms: the cycloalkyl group may be unsaturated,and may be fused to another ring that can be saturated, unsaturated oraromatic, provided the ring atom of the cycloalkyl group that isconnected to the molecular formula of interest is not an aromatic ringcarbon. Unless otherwise provided, cycloalkyl refers to cyclichydrocarbon groups having between 3 and 9 ring carbon atoms or between 3and 7 ring carbon atoms. Preferably, cycloalkyl groups are saturatedmonocyclic rings having 3-7 ring atoms, such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl, unless otherwise specified.

A substituted cycloalkyl is a cycloalkyl group substituted by one, ortwo, or three, or more than three substituents, up to the number ofhydrogens on the unsubstituted group. Typically, a substitutedcycloalkyl will have 1-4 substituents unless otherwise specified.Suitable substituents, unless otherwise specified, are independentlyselected from the group consisting of halogen, hydroxyl, thiol, cyano,nitro, oxo, C1-C4-alkylimino, C1-C4-alkoximino, hydroxyimino,C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy,C1-C4-thioalkyl, C2-C4-alkenyloxy, C2-C4-alkynyloxy,C1-C4-alkylcarbonyl, carboxy, C1-C4-alkoxycarbonyl, amino,C1-C4-alkylamino, di-C1-C4-alkylamino, C1-C4-alkylaminocarbonyl,di-C1-C4-alkylaminocarbonyl, C1-C4-alkylcarbonylamino,C1-C4-alkylcarbonyl(C1-C4-alkyl)amino, C1-C4-alkylsulfonyl,C1-C4-alkylsulfamoyl, and C1-C4-alkylaminosulfonyl, where each of theaforementioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl, alkoxyresidues) may be further substituted by one or more groups independentlyselected at each occurrence from the list of substituents for ‘alkyl’groups herein. Preferred substituents for a cycloalkyl group includeC1-C4 alkyl and the substituent groups listed above as suitablesubstituents for alkyl groups.

Exemplary monocyclic hydrocarbon groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like. Exemplary bicyclic hydrocarbon groups includebornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2,1,1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groupsinclude adamantyl and the like.

Similarly, each cycloalkyl part of other groups like “cycloalkyloxy”,“cycloalkoxyalkyl”, “cycloalkoxycarbonyl”, “cycloalkoxy-carbonylalkyl”,“cycloalkylsulfonyl”, “halocycloalkyl” shall have the same meaning asdescribed in the above-mentioned definition of “cycloalkyl”. When usedin these terms, the cycloalkyl is typically a monocyclic 3-7 carbonring, that is unsubstituted or substituted with 1-2 groups. Whenoptionally substituted, the substituents are typically selected fromC1-C4 alkyl and those set forth above as suitable for alkyl groups.

As used herein, the term “aryl” refers to an aromatic hydrocarbon grouphaving 6-14 carbon atoms in the ring portion. Typically, aryl ismonocyclic, bicyclic or tricyclic aryl having 6-14 carbon atoms, often6-10 carbon atoms, e.g., phenyl or naphthyl. Furthermore, the term“aryl” as used herein, refers to an aromatic substituent which can be asingle aromatic ring, or multiple aromatic rings that are fusedtogether. Non-limiting examples include phenyl, naphthyl and1,2,3,4-tetrahydronaphthyl, provided the tetrahydronaphthyl is connectedto the formula being described through a carbon of the aromatic ring ofthe tetrahydronaphthyl group. Unless otherwise indicated, a preferredaryl group is phenyl.

A substituted aryl is an aryl group substituted by 1-5 (such as one, ortwo, or three) substituents independently selected from the groupconsisting of hydroxyl, thiol, cyano, nitro, C₁-C₄-alkyl, C2-C₄-alkenyl,C₂-C₄-alkynyl, C₁-C₄-alkoxy, C₁-C₄-thioalkyl, C₂-C₄-alkenyloxy,C₂-C₄-alkynyloxy, halogen, C₁-C₄-alkylcarbonyl, carboxy,C₁-C₄-alkoxycarbonyl, amino, C₁-C₄-alkylamino, di-C₁-C₄-alkylamino,C₁-C₄-alkylaminocarbonyl, di-C₁-C₄-alkylaminocarbonyl,C₁-C₄-alkylcarbonylamino, C₁-C₄-alkylcarbonyl(C₁-C₄-alkyl)amino,C₁-C₄-alkylsulfonyl, sulfamoyl, C₁-C₄-alkylsulfamoyl, andC₁-C₄-alkylaminosulfonyl where each of the aforementioned hydrocarbongroups (e.g., alkyl, alkenyl, alkynyl, alkoxy residues) may be furthersubstituted by one or more groups independently selected at eachoccurrence from the groups listed above as suitable substituents foralkyl groups. Preferred substituents for a substituted aryl group areC₁₋₄ alkyl and those groups named above as suitable substituents foralkyl groups, excluding divalent groups such as oxo.

Similarly, each aryl part of other groups like “aryloxy”,“aryloxyalkyl”, “aryloxycarbonyl”, “aryloxy-carbonylalkyl” shall havethe same meaning as described in the above-mentioned definition of“aryl”.

As used herein, the term “heterocyclyl” refers to a heterocyclic radicalthat is saturated or partially unsaturated but not aromatic, and can bea monocyclic or a polycyclic ring (in case of a polycyclic ringparticularly a bicyclic, tricyclic or spirocyclic ring); and has 3 to14, more commonly 4 to 10, and most preferably 5 or 6 ring atoms;wherein one or more, preferably one to four, especially one or two ringatoms are heteroatoms independently selected from O, S and N (theremaining ring atoms therefore being carbon). Even if it is describedas, e.g., a C5-6 atom ring, a heterocycle contains at least oneheteroatom as a ring atom with the other ring atoms being carbon, andhas the number of ring atoms stated, e.g. 5-6 in this example.Preferably, a heterocyclyl group has one or two such heteroatoms as ringatoms, and preferably the heteroatoms are not directly connected to eachother. The bonding ring (i.e. the ring connecting to the Formula ofinterest) preferably has 4 to 12, especially 5 to 7 ring atoms unlessotherwise specified. The heterocyclic group can be fused to an aromaticring, provided the atom of the heterocyclic group attached to theFormula of interest is not aromatic. The heterocyclic group can beattached to the Formula of interest via a heteroatom (typicallynitrogen) or a carbon atom of the heterocyclic group. The heterocyclylcan include fused or bridged rings as well as spirocyclic rings, andonly one ring of a polycyclic heterocyclic group needs to contain aheteroatom as a ring atom. Examples of heterocycles includetetrahydrofuran (TFIF), dihydrofuran, 1,4-dioxane, morpholine,1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine,imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran,oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane,thiomorpholine, and the like.

A substituted heterocyclyl is a heterocyclyl group independentlysubstituted by 1-5 (such as one, or two, or three) substituents selectedfrom the substituents described above for a cycloalkyl group.

Similarly, each heterocyclyl part of other groups like“heterocyclyloxy”, “heterocyclyloxyalkyl”, “heterocyclyloxycarbonyl”shall have the same meaning as described in the above-mentioneddefinition of “heterocyclyl”.

As used herein, the term “heteroaryl” refers to a 5-14 memberedmonocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to8 heteroatoms as ring members, with the remaining ring atoms beingcarbon, and the heteroatoms are selected from N, O and S. Typically, theheteroaryl is a 5-10 membered ring system, especially a 5-6 memberedmonocyclic or an 8-10 membered bicyclic group. Typical heteroaryl groupsinclude 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or5-imidazolyl, 1-, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-,4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl,3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, 1- or 2-tetrazolyl,2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl,2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl.

The term “heteroaryl” also refers to a group in which a heteroaromaticring is fused to one or more aryl, cycloalkyl, or heterocyclyl rings.Non-limiting examples include 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-,or 7-benzothiazolyl.

A substituted heteroaryl is a heteroaryl group containing one or moresubstituents, typically one or two substituents, selected from thesubstituents described above as suitable for an aryl group.

Similarly, each heteroaryl part of other groups like “heteroaryloxy”,“heteroaryloxyalkyl”, “heteroaryloxycarbonyl” shall have the samemeaning as described in the above-mentioned definition of “heteroaryl”.

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments of thepresent invention. The following enumerated embodiments arerepresentative of aspects of the invention:

In one embodiment, the invention provides compounds of Formula (A):

or a pharmaceutically acceptable salt thereof, wherein:

Y is a group of the formula

wherein the dashed line represents a bond connecting Y to the tricycliccore of Formula (A);

G is H or a group selected from —C(O)R⁰, —C(O)—OR⁰, —C(R^(G))₂—O—C(O)R⁰,—C(R^(G))₂—O—C(O)—OR⁰, —C(O)—N(R⁰)₂, and —C(R^(G))₂—O—C(O)N(R⁰)₂, whereeach R⁰ is independently FI or a group selected from C₁-C₆ alkyl,phenyl, pyridyl, C₃-C₇ cycloalkyl, and a 3-6 membered heterocyclic ringcontaining one or two heteroatoms selected from N, O and S as ringmembers; and each R⁰ that is not H is optionally substituted with one ortwo groups selected from halo, CN, —OH, amino, C₁₋₄ alkyl, phenyl,C₁₋₄alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

-   -   and each R^(G) is independently selected from H and C₁₋₄ alkyl;

R¹ is H, halo, CN, COOR*, —CONR*₂, or C₁-C₆ alkyl optionally substitutedwith one or two groups selected from —OR* and —NR*₂, C₁-C₄ haloalkyl;

-   -   R* is independently at each occurrence H or C₁-C₆ alkyl        optionally substituted with —OR or —NR₂;

Z¹ is N, and Z² is C(R)₂;

-   -   or Z¹ is CH, and Z² is NR, O, S, or CH₂;

Z³ is CH₂, Q, —CH₂—CH₂—, -Q-CH₂—, —CH₂-Q-, —CH₂-Q-CH₂— or —CH₂—CH₂—CH₂—;

Q is selected from —NR—, O, S, SO, and SO₂;

R² is selected from H, halo, CN, C₁₋₄ alkyl optionally substituted withup to three groups independently selected from halo, CN, C₁₋₄ alkyl,—OR, C₁₋₄ haloalkoxy, —NR₂, and C₁₋₄ haloalkyl, OR, and C₁-C₄ haloalkyl;

each R³ is a substituent optionally present on any carbon atom of thering containing Z² and Z³, and is independently selected from —OR, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, oxo, CN, —NR₂, and C₁₋₄ alkyl optionallysubstituted with up to three groups independently selected from halo,CN, C₁₋₄ alkyl, —OR, C₁₋₄ haloalkoxy, —NR₂, and C₁₋₄ haloalkyl;

n is 0-2;

Ar¹ and Ar² each independently represent phenyl or a 5-6 memberedheteroaryl ring containing 1-3 heteroatoms selected from N, O and S asring members, and are each independently substituted with up to threegroups selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, C₂₋₄alkyne, and CN;

-   -   and Ar¹ and Ar² are optionally linked together by a bridge of        the formula —C(R^(L))₂-L- to form a tricyclic group, wherein Ar¹        and Ar² are each optionally substituted by up to two groups        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkyne, and CN;

R is independently at each occurrence H or C₁-C₄ alkyl optionallysubstituted with up to three groups independently selected from halo,OH, oxo, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄haloalkyl;

-   -   L is selected from S, S═O, SO₂, O, NR, C(R^(L))₂ and CF₂; and    -   and each R^(L) is independently H or C₁₋₂ alkyl.

Compounds of Formula (A) where G is not H can act as pro-drugs that arereadily converted in vivo into compounds where G is H.

In one embodiment of the compounds of Formula (A), G is H.

In another embodiment of the compounds of Formula (A), G is selectedfrom —C(O)R⁰, —C(O)—OR⁰, —C(R^(G))₂—O—C(O)R⁰, —C(R^(G))₂—O—C(O)—OR⁰,—C(O)—N(R⁰)₂, and —C(R^(G))₂—O—C(O)N(R⁰)₂, where each R⁰ isindependently H or a group selected from C₁-C₄ alkyl, phenyl, pyridyl,C₃-C₇ cycloalkyl, and a 3-6 membered heterocyclic ring containing one ortwo heteroatoms selected from N, O and S as ring members; and each Rthat is not H is optionally substituted with one or two groups selectedfrom halo, CN, —OH, amino, C₁₋₄ alkyl, phenyl, C₁₋₄alkoxy, C₁₋₄haloalkyl, and C₁₋₄ haloalkoxy.

In certain of the preceding embodiments, G is selected from —C(O)R⁰,—C(O)—OR⁰, —C(R^(G))₂—O—C(O)R⁰, and —C(R^(G))₂—O—C(O)—OR⁰, where each R⁰is independently H or C₁-C₄ alkyl, and each R^(G) is H or C₁-C₄ alkyl.In some of these embodiments, each R^(G) is H and R⁰ is C₁-C₄ alkyl.

In certain of the preceding embodiments, the compound of Formula (A) isof the formula:

or a pharmaceutically acceptable salt thereof.

In certain compounds of this formula, Z² is CH2, Z³ is CH2, n is 0, 1 or2, and each R³ is Me.

In another embodiment (Embodiment 1), the invention provides compoundsof Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, halo, CN, COOR*, —CONR*₂, or C₁-C₆ alkyl optionally substitutedwith one or two groups selected from —OR* and —NR*₂, C₁-C₄ haloalkyl;

-   -   R* is independently at each occurrence H or C₁-C₆ alkyl        optionally substituted with —OR or —NR₂;

Z¹ is N, and Z² is C(R)₂;

-   -   or Z¹ is CH, and Z² is NR, O, S, or CH₂;

Z³ is CH₂, Q, —CH2-CH2-, -Q-CH2-, —CH2-Q-, —CH2-Q-CH2- or —CH2-CH2-CH2-;

Q is selected from —NR—, O, S, SO, and SO₂;

R² is selected from H, halo, CN, C₁₋₄ alkyl optionally substituted withup to three groups independently selected from halo, CN, C₁₋₄ alkyl,—OR, C₁₋₄ haloalkoxy, —NR₂, and C₁₋₄ haloalkyl, OR, and C₁-C₄ haloalkyl;

each R³ is a substituent optionally present on any carbon atom of thering containing Z² and Z³, and is independently selected from —OR, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, oxo, CN, —NR₂, and C₁₋₄ alkyl optionallysubstituted with up to three groups independently selected from halo,CN, C₁₋₄ alkyl, —OR, C₁₋₄ haloalkoxy, —NR₂, and C₁₋₄ haloalkyl;

n is 0-2;

Ar¹ and Ar² each independently represent phenyl or a 5-6 memberedheteroaryl ring containing 1-3 heteroatoms selected from N, O and S asring members, and are each independently substituted with up to threegroups selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, C₂₋₄alkyne, and CN;

-   -   and Ar¹ and Ar² are optionally linked together by a bridge of        the formula —C(R^(L))₂-L- to form a tricyclic group, wherein Ar¹        and Ar² are each optionally substituted by up to two groups        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkyne, and CN;

R is independently at each occurrence H or C₁-C₄ alkyl optionallysubstituted with up to three groups independently selected from halo,OH, oxo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ haloalkyl;

-   -   L is selected from S, S═O, SO₂, O, NR, C(R^(L))₂ and CF₂; and    -   and each R^(L) is independently H or C₁₋₂ alkyl.    -   In a preferred embodiment of any of the compounds of Formula (G)        or Formula (I) in the preceding embodiments, if Z² is NR, O or        S, then Z³ is CH₂, CH₂CH₂, or CH₂CH₂CH₂.

The following enumerated embodiments describe and illustrate certainaspects of the invention.

2. A compound according to embodiment 1, or any of the embodiments ofFormula (A), or a pharmaceutically acceptable salt thereof, wherein Z¹is CH.

3. A compound according to embodiment 1 or embodiment 2, or any of theembodiments of Formula (A), or a pharmaceutically acceptable saltthereof, wherein Z¹ is N.

4. A compound according to any one of embodiments 1 to 3, or any of theembodiments of Formula (A), or a pharmaceutically acceptable saltthereof, wherein Z² is CH₂ or —CH₂—CH₂—.

5. A compound according to any of the preceding embodiments or apharmaceutically acceptable salt thereof, wherein Z³ is CH₂, —CH₂—CH₂—,—CH₂—CH₂—CH₂—, —CH₂—O—, or O.

6. A compound according to any of the preceding embodiments or apharmaceutically acceptable salt thereof, wherein R¹ is H.

7. A compound according to any of the preceding embodiments or apharmaceutically acceptable salt thereof, wherein R² is H.

8. A compound according to any of the preceding embodiments or apharmaceutically acceptable salt thereof, wherein Ar¹ and Ar² are bothphenyl and are each independently substituted with up to two groupsselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, C₂₋₄alkyne, and CN.

9. A compound of any of the preceding embodiments, which is of theformula:

wherein Y represents a group selected from

wherein each R^(y) is independently selected from H, halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄alkyne, and CN,

or a pharmaceutically acceptable salt thereof.

10. A compound of embodiment 9, or a pharmaceutically acceptable saltthereof, which is of the formula

wherein Z¹ is N or CH; andZ³ is CH₂ or —CH₂—CH₂—.

11. A compound of embodiment 1, or any of the embodiments of Formula(A), which is selected from the group consisting of Examples 1-149, or apharmaceutically acceptable salt thereof. Each of the compounds of theexamples is a specific embodiment of the invention, thus the inventionprovides a compound selected from:

-   1    12-benzhydryl-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   2    12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   3    12-(bis(4-chlorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   4    12-(bis(3-chlorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   5    12-(bis(4-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   6 13-benzhydryl-4-hydroxy-8,9,10,11-tetrahydro-7H,    13H-pyridazino[1′,6′:4,5][1,2,4]triazino[1,2-a][1,2]diazepine-3,5-dione;-   7    13-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,10,11-tetrahydro-7H,13H-pyridazino[1′,6′:4,5][1,2,4]triazino[1,2-a][1,2]diazepine-3,5-dione;-   8    (R)-12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   9    (S)-12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   10    (9aR,10S)-10-benzhydryl-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   11    (9aR,10R)-10-benzhydryl-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1    2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   12    (9aS,10R)-10-benzhydryl-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   13 (9aS,10S)-10-benzhydryl-4-hydroxy-8,9,9a,    10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   14    (9aR,10S)-10-((R)-(3-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   15 (9aR,10R)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,    10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   16    (9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   17    (9aS,10R)-10-((S)-(3-chlorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   18 (10aS,11R)-11-benzhydryl-4-hydroxy-7,8,10a, 11-tetrahydro-1    OH-pyridazino[1′,6′:4,5]pyrazino[2,1-c][1,4]oxazine-3,5-dione;-   19A    12-benzhydryl-7-hydroxy-3,4,12,12a-tetrahydro-2H-pyridazino[1′,6′:4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione;-   19B    12-benzhydryl-7-hydroxy-3,4,12,12a-tetrahydro-2H-pyridazino[1′,6′:4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione;-   20    11-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9-dihydro-7H,11H-pyrazolo[1,2-a]pyridazino[1,6-d][1,2,4]triazine-3,5-dione;-   21    12-(1,1-diphenylethyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   22    12-(bis(2-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   23A    12-benzhydryl-4-hydroxy-10-methyl-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   23B    12-benzhydryl-4-hydroxy-10-methyl-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   24    12-benzhydryl-4-hydroxy-7-methyl-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   25A    12-benzhydryl-4-hydroxy-7,10-dimethyl-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   25B    12-benzhydryl-4-hydroxy-7,10-dimethyl-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   26A    12-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   26B    12-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   27A    12-(6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   27B    12-(6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   28A    12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   28B    12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   29    (S)-12-benzhydryl-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   30    (S)-12-(bis(4-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   31    (R)-12-(bis(4-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione;-   32    (9aR,10S)-10-((R)-(2-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   33    (9aR,10S)-10-((R)-(3,4-difluorophenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   34    (9aR,10S)-10-((S)-(3,4-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   35    (9aR,10S)-10-((R)-(2-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   36    (9aR,10S)-10-((S)-(3,5-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   37    (9aR,10S)-10-((S)-(4-fluoro-2-methylphenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   38    (9aR,10S)-10-((S)-(3,4-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   39    (9aR,10S)-10-((R)-(2-fluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   40    (9aR,10S)-10-((R)-(3,5-difluorophenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   41    (9aR,10S)-10-((R)-(4-fluoro-2-methylphenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   42    (9aR,10S)-10-((R)-(2-fluorophenyl)(2-methoxyphenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   43    (9aR,10S)-10-((R)-(2-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   44    (9aR,10S)-10-(bis(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   45    (9aR,10S)-10-((R)-(3,5-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   46    (9aR,10S)-10-((R)-(2,6-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   47    (9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   48    (9aR,10S)-10-((R)-(2,6-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   49    (9aR,10S)-10-((R)-(2,6-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   50    (9aR,10S)-10-((S)-(3-fluorophenyl)(3,4,5-trifluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   51    (9aR,10S)-10-((S)-(2-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   52    (9aR,10S)-10-((R)-(3,4-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   53    (9aR,10S)-10-((S)-(3,4-difluorophenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   54    (9aR,10S)-10-((S)-(3,5-difluorophenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   55    (9aR,10S)-10-((S)-(2-fluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   56    (9aR,10S)-10-((S)-(4-fluoro-2-methylphenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   57    (9aR,10S)-10-((S)-(2-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   58    (9aR,10S)-10-((S)-(4-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   59    (9aR,10S)-10-((S)-(3-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   60    (9aR,10S)-10-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   61    (9aR,10S)-10-((S)-(2,6-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   62    (9aR,10S)-10-((S)-(2,6-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   63    (9aR,10S)-10-((S)-(2,6-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   64    (9aR,10S)-10-((R)-(3-fluorophenyl)(3,4,5-trifluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   65    (9aR,10S)-10-((R)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   66    (9aR,10S)-10-((R)-(4-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   67    (9aR,10R)-10-((S)-(4-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   68    (9aR,10S)-10-((R)-(4-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   69    (9aR,10S)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   70    (9aR,10S)-10-((S)-(3,4-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   71    (9aR,10S)-10-((S)-(4-fluoro-2-methylphenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   72    (9aR,10S)-10-((R)-(2,3-difluorophenyl)(2,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   73    (9aR,10R)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   74    (9aR,10S)-10-((R)-(2,3-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   75    (9aR,10S)-10-((S)-(3,5-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   76    (9aR,10S)-10-((S)-(3,4-difluorophenyl)(3,5-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   77    (9aR,10S)-10-((R)-(3,4-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   78    (9aR,10S)-10-(bis(3,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   79    (9aR,10S)-10-(bis(2,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   80    (9aR,10S)-10-((R)-(2,5-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   81    (9aR,10S)-10-((R)-(2,5-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   82    (9aR,10S)-10-((R)-(2,5-difluorophenyl)(3,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   83    (9aR,10S)-10-((S)-(3,5-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   84    (9aR,10S)-10-((R)-(2,5-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   85    (9aR,10S)-10-((R)-(2,4-difluorophenyl)(3,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   86    (9aR,10S)-10-((S)-(4-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   87    (9aR,10S)-10-((R)-(2,4-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   88    (9aR,10S)-10-((R)-(2,4-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   89    (9aR,10S)-10-((R)-(2,4-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   90    (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   91    (9aR,10S)-10-((S)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   92    (9aR,10S)-10-((R)-(4-fluoro-2-methylphenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   93    (9aR,10S)-10-((R)-(3,4-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   94    (9aR,10S)-10-((R)-(3,4-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-2-(hydroxymethyl)-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   95    (9aR,10S)-10-((S)-(2,3-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   96    (9aR,10S)-10-((R)-(3,4-difluorophenyl)(3,5-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   97    (9aR,10S)-10-((R)-(3,5-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   98    (9aR,10S)-10-((S)-(2,5-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   99    (9aR,10S)-10-((S)-(2,5-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   100    (9aR,10S)-10-((S)-(2,5-difluorophenyl)(3,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   101    (9aR,10S)-10-((R)-(3,5-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   102    (9aR,10S)-10-((S)-(2,4-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   103    (9aR,10S)-10-((S)-(2,4-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   104    (9aR,10S)-10-((S)-(2,4-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   105    (9aR,10S)-10-((S)-(2,4-difluorophenyl)(3,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   106 10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,    10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   107    4-((R)-(3-fluorophenyl)((9aR,10S)-4-hydroxy-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-10-yl)methyl)benzonitrile;-   108    (9aR,10S)-10-((S)-(4-chlorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   109    (9aR,10S)-10-((R)-(3-chlorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   110    (9aR,10S)-10-((S)-(2-bromophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   111    (9aR,10S)-10-((R)-(2-bromophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   112    (9aR,10S)-10-((S)-(3-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   113    (9aR,10S)-10-((S)-(3-chlorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   114    (9aR,10S)-10-((R)-(3-chlorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   115    (9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   116    (9aR,10R)-10-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   117    (7S,9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   118    (7S,9aR,10R)-10-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   119    (7R,9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   120    (7R,9aR,10R)-10-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   121    (8S,9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8-methoxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   122    (8R,9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8-methoxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   123 (10aR,11S)-11-benzhydryl-4-hydroxy-7,8,10a,    11-tetrahydro-10H-pyridazino[1′,6′:4,5]pyrazino[2,1-c][1,4]oxazine-3,5-dione;-   124A    11-benzhydryl-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   124B    11-benzhydryl-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   125A    11-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   125B    11-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   126 11-benzhydryl-4-hydroxy-7,8,10a,    11-tetrahydro-10H-pyridazino[1′,6′:4,5]pyrazino[2,1-c][1,4]oxazine-3,5-dione;-   127    11-benzhydryl-4-hydroxy-7-methyl-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione;-   128    (9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl    3-methylbutanoate;-   129    (9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl    3-methylbutanoate;-   130    (9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl    acetate;-   131    (9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl    isobutyrate;-   132    (9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl    isopropyl carbonate;-   133    1-(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)ethyl    ethyl carbonate;-   134    (S)-((12-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,7,8,9,10-hexahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazin-4-yl)oxy)methyl    ethyl carbonate;-   135    (((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl    (2-methoxyethyl) carbonate;-   136    1-(((9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)ethyl    ethyl carbonate;-   137    (((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl    methyl carbonate;-   138    (((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl    ethyl carbonate;-   139    (((9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl    methyl carbonate;-   140    (((9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl    ethyl carbonate;-   141    (((9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl    isopropyl carbonate;-   142    (((9aR,10S)-10-((R)-(4-fluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl    methyl carbonate;-   143    (((9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl    pivalate;-   144    (S)-((12-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,7,8,9,10-hexahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazin-4-yl)oxy)methyl    methyl carbonate;-   145    (((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl    L-valinate;-   146    (9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl    dimethylcarbamate;-   147    (((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl    ethyl(methyl)carbamate;-   148 methyl    2-(((((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)(ethoxy)phosphoryl)oxy)acetate;    -   and-   149 methyl    2-((((((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methoxy)carbonyl)oxy)-2-methylpropanoate;    and the pharmaceutically acceptable salts of these compounds.

12. A pharmaceutical composition comprising a compound of any of thepreceding embodiments or a pharmaceutically acceptable salt thereof andone or more pharmaceutically acceptable carriers.

13. A combination comprising a therapeutically effective amount of acompound according to any one of embodiments 1 to 11, or any of theembodiments of Formula (A), or a pharmaceutically acceptable saltthereof and one or more therapeutically active co-agents.

14. A method of treating influenza, comprising administering to asubject in need thereof a therapeutically effective amount of a compoundof any of embodiments 1-11, or any of the embodiments of Formula (A), ora pharmaceutically acceptable salt thereof.

15. A compound according to any one of embodiments 1 to 11, or any ofthe embodiments of Formula (A), or a pharmaceutically acceptable saltthereof, for use as a medicament.

16. A compound according to any one of embodiments 1 to 11, or any ofthe embodiments of Formula (A), or a pharmaceutically acceptable saltthereof, for use in the treatment of influenza.

17. Use of a compound according to any one of embodiments 1 to 11, orany of the embodiments of Formula (A), or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for the treatment ofinfluenza.

In some embodiments, the compound of Formula (A) is a compound of one ofthe following formulas:

-   -   wherein G is H, or G is selected from —C(O)R⁰, —C(O)—OR⁰,        —C(R^(G))₂—O—C(O)R⁰, and —C(R^(G))₂—O—C(O)—OR⁰, where each R⁰ is        independently H or C₁-C₄ alkyl, and each R^(G) is H or C₁-C₄        alkyl. In some of these embodiments, each R^(G) is H and R⁰ is        C₁-C₄ alkyl;        n is 0, 1 or 2;        each R³ represents Me, OH, OMe, or halo; and Y represents

wherein each R^(y) is independently selected from F, Cl, Me, OMe, CF₃,OCF₃, and CN; and each q is independently 0, 1, or 2.

In some embodiments, the compound of Formula (I) is a compound of one ofthe following formulas:

wherein n is 0, 1 or 2;each R³ represents Me, OH, OMe, or halo; and Y represents

wherein each R^(y) is independently selected from FI, F, Cl, Me, OMe,CF₃, OCF₃, and CN.

As used herein, the term “an optical isomer” or “a stereoisomer” refersto any of the various stereo isomeric configurations which may exist fora given compound of the present invention and includes geometricisomers. It is understood that a substituent may be attached at a chiralcenter of a carbon atom. The term “chiral” refers to molecules whichhave the property of non-superimposability on their mirror imagepartner, while the term “achiral” refers to molecules which aresuperimposable on their mirror image partner. Therefore, the inventionincludes enantiomers, diastereomers or racemates of the compound.“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term is used to designate a racemic mixture whereappropriate. “Diastereoisomers” are stereoisomers that have at least twoasymmetric atoms, but which are not mirror-images of each other. Theabsolute stereochemistry is specified according to theCahn-Ingold-Prelog ‘R-S’ system. When a compound is a pure enantiomer,the stereochemistry at each chiral carbon may be specified by either Ror S. Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Certain compounds described herein contain one ormore asymmetric centers or axes and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)-.

Depending on the choice of the starting materials and synthesisprocedures, the compounds can be present in the form of one of thepossible isomers or as mixtures thereof, for example as pure opticalisomers, or as isomer mixtures, such as racemates and diastereoisomermixtures, depending on the number of asymmetric carbon atoms. Thepresent invention is meant to include all such possible isomers,including racemic mixtures, diasteriomeric mixtures and optically pureforms. Optically active (R)- and (S)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques. If the compound contains a double bond, the substituent maybe E or Z configuration unless specified. If the compound contains adi-substituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration, unless otherwise specified. All tautomeric formsare also intended to be included.

In many cases, the compounds of the present invention are capable offorming acid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. As used herein, the terms“salt” or “salts” refers to an acid addition or base addition salt of acompound of the invention. “Salts” include in particular “pharmaceuticalacceptable salts”. The term “pharmaceutically acceptable salts” refersto salts that retain the biological effectiveness and properties of thecompounds of this invention and, which typically are not biologically orotherwise undesirable.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlorotheophyllinate, citrate, ethanedisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts. Lists of additional suitable salts can be found,e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., MackPublishing Company, Easton, Pa., (1985); and in “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002).

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic or organic bases and can have inorganic or organiccounterions.

Inorganic counterions for such base salts include, for example, ammoniumsalts and metals from columns I to XII of the periodic table. In certainembodiments, the counterion is selected from sodium, potassium,ammonium, alkylammonium having one to four C₁-C₄ alkyl groups, calcium,magnesium, iron, silver, zinc, and copper; particularly suitable saltsinclude ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Suitable organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, tetrahydrofuran, toluene, chloroform, dichloromethane,methanol, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable.

Any formula given herein is also intended to represent unlabeled forms(i.e., compounds wherein all atoms are present at natural isotopicabundances, and not isotopically enriched) as well as isotopicallyenriched or labeled forms of the compounds. Isotopically enriched orlabeled compounds have structures depicted by the formulas given hereinexcept that at least one atom of the compound is replaced by an atomhaving an atomic mass or mass number different from the atomic mass orthe atomic mass distribution that occurs naturally. Examples of isotopesthat can be incorporated into enriched or labeled compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl, and ¹²⁵I. The invention includes variousisotopically labeled compounds as defined herein, for example those inwhich radioactive isotopes, such as ³H and ¹⁴C, or those in whichnon-radioactive isotopes, such as ²H and ¹³C, are present at levelssignificantly above the natural abundance for these isotopes. Theseisotopically labeled compounds are useful in metabolic studies (e.g.,with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H),detection or imaging techniques, such as positron emission tomography(PET) or single-photon emission computed tomography (SPECT) includingdrug or substrate tissue distribution assays, or in radioactivetreatment of patients. In particular, an ¹⁸F labeled compound may beparticularly desirable for PET or SPECT studies. Isotopically-labeledcompounds of formula (I) can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the accompanying Examples using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., 2H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Theconcentration of such a heavier isotope, specifically deuterium, may bedefined by the isotopic enrichment factor. The term “isotopic enrichmentfactor” as used herein means the ratio between the isotopic abundanceand the natural abundance of a specified isotope. If a substituent in acompound of this invention is denoted deuterium, such compound has anisotopic enrichment factor for each designated deuterium atom of atleast 3500 (52.5% deuterium incorporation at each designated deuteriumatom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5%deuterium incorporation), at least 5000 (75% deuterium incorporation),at least 5500 (82.5% deuterium incorporation), at least 6000 (90%deuterium incorporation), at least 6333.3 (95% deuterium incorporation),at least 6466.7 (97% deuterium incorporation), at least 6600 (99%deuterium incorporation), or at least 6633.3 (99.5% deuteriumincorporation).

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D20, d6-acetone, d6-DMSO, as well as solvates withnon-enriched solvents.

Compounds of the invention, i.e., compounds of formula (I) that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of formula (I) by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula (I) with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of formula (I).

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drug stabilizers, binders, excipients, disintegrationagents, lubricants, sweetening agents, flavoring agents, dyes, and thelike and combinations thereof, as would be known to those skilled in theart for use in a pharmaceutical composition for administration to ahuman subject (see, for example, Remington: The Science and Practice ofPharmacy, 22nd ed.). Except insofar as any conventional carrier isincompatible with the active ingredient, its use in the therapeutic orpharmaceutical compositions is contemplated.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response in asubject, for example, an amount sufficient to reduce of one or moresymptoms, alleviate conditions, slow or delay disease progression, orprevent a disease, etc. In one non-limiting embodiment, the term “atherapeutically effective amount” refers to the amount of a compound ofthe present invention that, when administered to a subject, is effectiveto reduce one or more symptoms associated with an influenza virusinfection, or to shorten the duration of the symptomatic stage of aninfluenza virus infection, or to slow the progression of an influenzavirus infection, or to reduce or stop the exacerbation of an underlyingcondition by an influenza virus infection.

In another non-limiting embodiment, the term “a therapeuticallyeffective amount” refers to the amount of the compound of the presentinvention that, when administered to a cell, or a tissue, or anon-cellular biological material, or a medium, is effective to cause astatistically significant reduction in rate of replication orproliferation of a strain of orthomyxovirus.

As used herein, the term “subject” refers to an animal. Typically, thesubject is a human.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the development or progression of the disease or disorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess ofeither the (R)- or (S)-configuration; i.e., for optically activecompounds, it is often preferred to use one enantiomer to thesubstantial exclusion of the other enantiomer, so typically anenantiomeric purity of at least 95% is preferred. Substituents at atomswith unsaturated double bonds may, if possible, be present in cis- (Z)-or trans- (E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof. ‘Substantially pure’ or‘substantially free of other isomers’ as used herein means the productcontains less than 5%, and preferably less than 2%, of other isomersrelative to the amount of the preferred isomer, by weight.

Resulting mixtures of isomers can typically be separated on the basis ofthe physicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Racemates of final products or intermediates can typically be resolvedinto the optical antipodes by known methods, e.g., by separation of thediastereomeric salts thereof, obtained with an optically active acid orbase, and liberating the optically active acidic or basic compound. Inparticular, a basic moiety may thus be employed to resolve the compoundsof the present invention into their optical antipodes, e.g., byfractional crystallization of a salt formed with an optically activeacid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaricacid, di-O,O′-p-toluoyl tartaric acid, mandelic acid, malic acid orcamphor-10-sulfonic acid. Racemic products can also be resolved bychiral chromatography, e.g., high pressure liquid chromatography (HPLC)using a chiral stationary phase.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier. In some embodiments, thepharmaceutical composition comprises at least two pharmaceuticallyacceptable excipients or carriers. Pharmaceutically acceptable carriersand other excipients are known to those of skill in the art, and may beselected, for example, from carriers and excipients used in approved(registered) formulated therapeutic agents that are administered viasimilar routes of administration. The pharmaceutical composition can beformulated for particular routes of administration such as oraladministration, parenteral administration, and rectal administration,and the like. In addition, the pharmaceutical compositions of thepresent invention can be made up in a solid form (including withoutlimitation capsules, tablets, pills, granules, powders orsuppositories), or in a liquid form (including without limitationsolutions, suspensions or emulsions). The pharmaceutical compositionscan be subjected to conventional pharmaceutical operations such assterilization and/or can contain conventional inert diluents,lubricating agents, or buffering agents, as well as adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers and buffers,etc.

In one embodiment, the compounds of the invention are formulated fororal delivery. Typically, these pharmaceutical compositions are tabletsor gelatin capsules comprising the active ingredient (at least onecompound of Formula (I)) together with one or more excipients selectedfrom:

a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine;

b) lubricants, e.g., silica, talcum, stearic acid, its magnesium orcalcium salt and/or polyethyleneglycol; for tablets also

c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone; if desired

d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt,or effervescent mixtures; and/or

e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor the manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems may pertain to an inhalation or to anintranasal application that may be suitable for use to treat influenza,for example, and may contain solubilizers, stabilizers, tonicityenhancing agents, buffers and preservatives. They may be convenientlydelivered in the form of a dry powder (either alone, as a mixture, forexample a dry blend with lactose, or a mixed component particle, forexample with phospholipids) from a dry powder inhaler or an aerosolspray presentation from a pressurized container, pump, spray, atomizeror nebulizer, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e. g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The compounds of formula (I), in free form or in salt form, exhibitvaluable pharmacological properties, e.g. they inhibit or preventreplication of orthomyxovirus, as indicated by test data provided in thenext sections, and are therefore indicated for therapy or for use asresearch chemicals, e.g. as tool compounds such as for the study ofreplication of an orthomyxovirus, particularly Influenza A, Influenza Bor Influenza C. Accordingly, compounds of the invention are useful inthe treatment of an infection caused by an orthymyxovirus, particularlyInfluenza A, Influenza B or Influenza C, especially in human subjects.In some embodiments, the subject to be treated is a human having or atrisk of contracting an influenza viral infection. For example, subjectshaving pre-existing conditions such as asthma or COPD that can begreatly exacerbated by an influenza infection may be treated with themethods or compounds of the invention before exhibiting symptoms of aninfluenza infection, especially if they are at risk of contractinginfluenza due to close proximity to persons such as family members whohave or appear to have influenza. In other embodiments, the subject fortreatment by the methods and compositions of the invention is onediagnosed as having symptoms consistent with an influenza infection. Inother embodiments, the subject may be a human who has been tested withknown diagnostic methods such as a Rapid Influenza Diagnostic Test(RIDT) or Reverse Transcriptase PCT (RT-PCR) methods to detect thepresence of influenza virus, and found to be infected with influenza,regardless of the presence of typical influenza symptoms.

As a further embodiment, the present invention provides the use of acompound of formula (I) or any of the embodiments within the scope ofFormula (I) as described herein, in therapy. In particular, thecompounds are suitable for use to treat a subject having or atparticularly high risk for an orthomyxovirus viral infection, especiallyInfluenza A, Influenza B, or Influenza C.

In another embodiment, the invention provides a method of treating adisease which is caused by an orthomyxovirus, comprising administrationof a therapeutically effective amount of a compound of formula (I) orany of the embodiments within the scope of Formula (I) as describedherein to a subject in need of such treatment. In some embodiments, thecompound of formula (I) is administered orally. In a further embodiment,the disease is selected from Influenza A, Influenza B, and Influenza C.The method typically comprises administering an effective amount of acompound as described herein, or a pharmaceutical composition comprisingan effective amount of such compound, to a subject in need of suchtreatment. The compound may be administered by any suitable method suchas those described herein, and the administration may be repeated atintervals which may be selected by a treating physician. In someembodiments, the compound or pharmaceutical composition is administeredorally.

Thus, as a further embodiment, the present invention provides the use ofa compound of formula (I) or any of the embodiments of such compoundsdescribed herein for the manufacture of a medicament. In a particularembodiment, the medicament is for treatment of an orthomyxovirusinfection, especially Influenza A, Influenza B, or Influenza C.

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more therapeuticco-agent(s). The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the co-agent(s).Suitable co-agents for use with the compounds of the invention includeantivirals active on influenza viruses, such as neuraminidase inhibitorsincluding oseltamivir, peramivir, zanamivir and laninamivir, laninamiviroctanoate, and adamantanes such as amantadine and rimantadine.Additional co-agents for use in these methods include an M2 proteininhibitor, a polymerase inhibitor, a PB2 inhibitor, favipiravir,fludase, ADS-8902, beraprost, Neugene®, ribavirin, CAS Reg. No.1422050-75-6, VX-787, Flu Mist Quadrivalent®, Fluarix® Quadrivalent,Fluzone® Quadrivalent, Flucelvax® and FluBlok®.

In one embodiment, the invention provides a product comprising acompound of formula (I) and at least one other therapeutic co-agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a viralinfection caused by an orthomyxovirus, particularly Influenza A,Influenza B or Influenza C. Products provided as a combined preparationinclude a composition comprising a compound of formula (I) and at leastone of the other therapeutic co-agent(s) together in the samepharmaceutical composition, or the compound of formula (I) and at leastone other therapeutic co-agent(s) in separate form, e.g. in the form ofa kit for use to treat a subject by the methods described herein.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) and another therapeuticco-agent(s). Suitable co-agents include antivirals active on influenzaviruses, such as neuraminidase inhibitors including oseltamivir,peramivir, zanamivir and laninamivir, and adamantanes such as amantadineand rimantadine. Optionally, the pharmaceutical composition may comprisea pharmaceutically acceptable carrier, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of formula (I). The other pharmaceutical composition maycontain one of the suitable co-agents. In one embodiment, the kitcomprises means for separately retaining said compositions, such as acontainer, divided bottle, or divided foil packet. An example of such akit is a blister pack, as typically used for the packaging of tablets,capsules and the like.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the therapeutic co-agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the therapeutic co-agent may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe therapeutic co-agent.

Accordingly, the invention provides the use of a compound of formula (I)for treating a viral infection caused by an orthomyxovirus, particularlyinfluenza, which may be Influenza A, Influenza B or Influenza C, whereinthe medicament is prepared for administration with a therapeuticco-agent. Typically in the methods of using the compounds of theinvention, the serotype of influenza is not identified before treatment.The invention also provides the use of therapeutic co-agent for treatinga disease or condition, wherein the medicament is administered with acompound of formula (I).

The invention also provides a compound of formula (I) for use in amethod of treating a viral infection caused by an orthomyxovirus,particularly Influenza A, Influenza B or Influenza C, wherein thecompound of formula (I) is prepared for administration with atherapeutic co-agent. The invention also provides another therapeuticco-agent for use in a method of treating a viral infection caused by anorthomyxovirus, particularly influenza, e.g., Influenza A, Influenza Bor Influenza C, wherein the therapeutic co-agent is prepared foradministration with a compound of formula (I). The invention alsoprovides a compound of formula (I) for use in a method of treating aviral infection caused by an orthomyxovirus, particularly Influenza A,Influenza B or Influenza C, wherein the compound of formula (I) isadministered with a therapeutic co-agent. The invention also provides atherapeutic co-agent for use in a method of treating a viral infectioncaused by an orthomyxovirus, particularly Influenza A, Influenza B orInfluenza C, wherein the a therapeutic co-agent is administered with acompound of formula (I).

The invention also provides the use of a compound of formula (I) fortreating a viral infection caused by an orthomyxovirus, particularlyinfluenza, e.g., Influenza A, Influenza B or Influenza C, wherein thepatient has previously (e.g. within 24 hours) been treated with anothertherapeutic agent. The invention also provides the use of anothertherapeutic agent for treating a viral infection caused by anorthomyxovirus, particularly Influenza A, Influenza B or Influenza C,wherein the patient has previously (e.g. within 24 hours) been treatedwith a compound of formula (I).

In one embodiment, the therapeutic co-agent is selected from antiviralspurported to be useful for treating infections caused by influenzaviruses, such as neuraminidase inhibitors including oseltamivir,peramivir, zanamivir and laninamivir, and adamantanes such as amantadineand rimantadine.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage containing about 1-1000 mg of active ingredient(s)for a human subject of about 50-70 kg, or about 1-500 mg, or about 1-250mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of activeingredients. The therapeutically effective dosage of a compound, thepharmaceutical composition, or the combinations thereof, is dependent onthe species of the subject, the body weight, age and individualcondition, the disorder or disease or the severity thereof beingtreated. A physician, clinician or veterinarian of ordinary skill canreadily determine the effective amount of each of the active ingredientsnecessary to prevent, treat or inhibit the progress of the disorder ordisease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 0.1-50 mg/kg.

The invention further includes processes to make the compounds ofFormula (I) as disclosed herein, and any variant of the presentprocesses, in which an intermediate product obtainable at any stagethereof is used as starting material and the remaining steps are carriedout, or in which the starting materials are formed in situ under thereaction conditions, or in which the reaction components are used in theform of their salts or optically pure material.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known to those skilled in theart.

Methods to synthesize compounds of Formula (I) are depicted in SchemesA-C and are illustrated by the Examples herein. Scheme A depicts a wayto prepare compounds wherein Z1 is N, Z2 is C(R)2, and Z3 is —CR2-CR2-,and should also enable synthesis of compounds with other Z3 linkages. Itbegins with a 5-hydroxypyridazine-4-one-3-carboxylic acid compound,where both the 5-hydroxy and the ring NH are protected with a suitableprotecting group that can readily be removed. The carboxylic acid iscondensed with a cyclic hydrazine linkage to provide the two outerrings. After deprotection of the ring nitrogen, the center ring isformed by condensation with an aldehyde.

Schemes B and C depict methods to make compounds of Formula (I) whereinZ¹ is CR, Z² is CR₂, and Z³ is CR₂.

Using these synthesis schemes and the examples provided, the skilledperson can prepare the compounds of Formula (I).

EXAMPLES

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Celsius. If not mentioned otherwise, all evaporations areperformed under reduced pressure, typically between about 15 mm Hg and100 mm Hg (about 20-133 mbar). The structure of final products,intermediates and starting materials is confirmed by standard analyticalmethods, e.g., microanalysis and spectroscopic characteristics, e.g.,MS, IR, NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesize thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art in view of the following examples.

Abbreviations

-   ATP adenosine 5′-triphosphate-   Bn benzyl-   BOC tertiary butyl carboxy-   br broad-   BSA bovine serum albumin-   d doublet-   dd doublet of doublets-   DCM dichloromethane-   DEAD diethyl azodicarboxylate-   DBAD di-tert-butyl azodicarboxylate-   DIBAL-H diisobutylaluminum hydride-   DIEA diethylisopropylamine-   DME 1,4-dimethoxyethane-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DTT dithiothreitol-   EDTA ethylenediamine tetraacetic acid-   ESI electrospray ionization-   EtOAc ethyl acetate-   FCC flash column chromatography-   h hour(s)-   HBTU    1-[bis(dimethylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)    3-oxide-   HOBt 1-hydroxy-7-azabenzotriazole-   HPLC high pressure liquid chromatography-   IR infrared spectroscopy-   LCMS liquid chromatography and mass spectrometry-   MeOH methanol-   MS mass spectrometry-   MW microwave-   m multiplet-   min minutes-   ml. milliliter(s)-   m/z mass to charge ratio-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NMP N-methyl pyrrolidinone-   NMR nuclear magnetic resonance-   ppm parts per million-   PyBOP benzotriazol-1-yloxytripyrrolidinophosphonium    hexafluorophosphate-   rac racemic-   rt room temperature-   s singlet-   SEM (2-(trimethylsilyl)ethoxy)methyl-   t triplet-   TBDMS t-butyldimethylsilyl-   TBDPS t-butyldiphenylsilyl-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TrisHCI aminotris(hydroxymethyl)methane hydrochloride

Example 1:12-benzhydryl-4-hydroxy-7,8,9,10-tetrahydro-3H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5(12H)-dioneIntermediate 1.1:1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylic Acid

To a suspension of ethyl5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylate hydrochloride(1.5 g, 4.83 mmol) in MeOH at RT was added NaOH (0.792 g, 19.79 mmol).Stirred at rt for 2 h. Benzyl bromide (2.067 ml, 17.38 mmol) was addedand the mixture stirred for 2 hours. The reaction was concentrated onthe rotovap, then added EtOAc and water. The mixture was then acidifiedwith 1 M HCl to pH 3. solid crashed out while adding HCl. filtered. Thewhite solid was washed with a small amount of EtOAc and water. The whitesolid collected on the filter was dried in vacuo to give1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid(1.1 g, 3.27 mmol, 67.7% yield), which was used without furtherpurification. MS m/z 337.3 (M+1).

Intermediate 1.2: Tert-butyl2-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)tetrahydropyridazine-1(2H)-carboxylate

To a solution of1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid(850 mg, 2.53 mmol) in DCM (Volume: 12.600 mL) at RT was added Huenig'sBase (1.170 mL, 6.70 mmol) and HATU (1249 mg, 3.29 mmol). The mixturewas stirred at RT for 30 min, then added tert-butyltetrahydropyridazine-1(2H)-carboxylate (518 mg, 2.78 mmol). The mixturewas stirred at RT for 16 h, diluted with DCM (10 mL) and washed withwater (10 mL), then brine (10 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated on the rotovap. The residue waspurified by ISCO (40 g silica gel column, 40-100% EtOAc in heptane) togive tert-butyl2-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)tetrahydropyridazine-1(2H)-carboxylate(1.22 g, 2.418 mmol, 96% yield) as a white foam. MS m/z 505.4 (M+1).

Intermediate 1.3: Tert-butyl2-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)tetrahydropyridazine-1(2H)-carboxylate

A solution of tert-butyl2-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)tetrahydropyridazine-1(2H)-carboxylate(220 mg, 0.436 mmol) in MeOH (Volume: 21.800 mL) was purged withnitrogen. Added a spatula tip of Pd—C (10%) (46.4 mg, 0.044 mmol) andattached a hydrogen balloon. The flask was evacuated and refilled withhydrogen (3 times) and then stirred vigorously at RT under a balloon ofhydrogen. After 30 min, the reaction was purged with nitrogen and thenfiltered through a plug of celite, using MeOH to wash through. Thefiltrate was concentrated in vacuo and used without furtherpurification. MS m/z 325.3 (M+1).

Example 1:12-benzhydryl-4-hydroxy-7,8,9,10-tetrahydro-3H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5(12H)-dione

Added 2,2-diphenylacetaldehyde (77 mg, 0.392 mmol) to a vial containingcrude tert-butyl2-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)tetrahydropyridazine-1(2H)-carboxylate(141 mg, 0.436 mmol) and a stir bar. TFA (Volume: 2 mL) was added andthe mixture was stirred at RT for 30 min. The reaction was concentratedin vacuo. The residue was purified by reverse-phase HPLC (MeCN/waterwith 0.1% TFA). The fractions containing product were combined, frozenand lyophilized to give12-benzhydryl-4-hydroxy-7,8,9,10-tetrahydro-3H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5(12H)-dione(19 mg, 0.036 mmol, 8.27% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 7.55-7.46 (m, 2H), 7.34 (s, 1H), 7.30 (dd, J=8.1, 1.6 Hz,4H), 7.25-7.10 (m, 4H), 6.33 (d, J=10.5 Hz, 1H), 4.62 (d, J=10.5 Hz,1H), 4.36-4.25 (m, 1H), 3.29-3.21 (m, 1H), 2.86 (td, J=11.1, 2.6 Hz,1H), 2.46-2.38 (m, 1H), 1.70-1.39 (m, 4H). MS m/z 403.4 (M+1).

Example 2.12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-3H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5(12H)-dione

This compound was made by the same process used to make Example 1. 1HNMR (400 MHz, DMSO-d6) δ 7.50-7.45 (m, 1H), 7.39 (s, 1H), 7.39-7.33 (m,2H), 7.32-7.13 (m, 3H), 7.12-6.94 (m, 2H), 6.41 (d, J=10.8 Hz, 1H), 4.82(d, J=10.7 Hz, 1H), 4.36-4.26 (m, 1H), 3.28-3.18 (m, 1H), 2.88 (td,J=11.0, 2.5 Hz, 1H), 2.39 (td, J=12.5, 3.1 Hz, 1H), 1.73-1.64 (m, 1H),1.51 (dddd, J=30.2, 15.0, 6.1, 3.3 Hz, 3H). MS m/z 439.3 (M+1).

Example 3.12-(bis(4-chlorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-3H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5(12H)-dione

This compound was made by the same process used to make Example 1. 1HNMR (400 MHz, DMSO-d6) δ 7.54 (d, J=8.5 Hz, 2H), 7.43-7.31 (m, 5H),7.30-7.23 (m, 2H), 6.36 (d, J=10.7 Hz, 1H), 4.78 (d, J=10.7 Hz, 1H),4.36-4.24 (m, 1H), 3.27-3.19 (m, 1H), 2.87 (td, J=11.1, 2.7 Hz, 1H),2.40 (td, J=12.5, 2.9 Hz, 1H), 1.72-1.62 (m, 1H), 1.62-1.38 (m, 3H). MSm/z 471.2 (M+1).

Example 4.12-(bis(3-chlorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-3H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5(12H)-dione

This compound was made by the same process used to make Example 1. 1HNMR (400 MHz, DMSO-d6) δ 7.64 (t, J=1.8 Hz, 1H), 7.52 (dt, J=7.8, 1.3Hz, 1H), 7.47 (q, J=1.4 Hz, 1H), 7.40 (d, J=3.1 Hz, 1H), 7.37 (m, 5H),6.44 (d, J=10.7 Hz, 1H), 4.83 (d, J=10.7 Hz, 1H), 4.37-4.25 (m, 1H),3.29-3.16 (m, 1H), 2.88 (td, J=11.2, 2.6 Hz, 1H), 2.44-2.29 (m, 1H),1.73-1.62 (m, 1H), 1.61-1.37 (m, 3H). MS m/z 471.2 (M+1).

Example 5.12-(bis(4-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-3H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5(12H)-dione

This compound was made by the same process used to make Example 1. 1HNMR (400 MHz, Solvent) 5 ppm 7.52 (s, 1H) 7.43-7.49 (m, 2H) 7.21-7.28(m, 2H) 7.04-7.13 (m, 2H) 6.88-6.95 (m, 2H) 6.12 (d, J=10.32 Hz, 1H)4.65 (d, J=10.37 Hz, 1H) 4.38-4.52 (m, 1H) 3.23 (dt, J=10.99, 3.26 Hz,1H) 2.88-2.99 (m, 1H) 2.68 (td, J=12.18, 4.16 Hz, 1H) 1.72-1.83 (m, 2H)1.56-1.70 (m, 2H). MS m/z 439.3 (M+1).

Example 6.13-benzhydryl-4-hydroxy-8,9,10,11-tetrahydropyridazino[1′,6′:4,5][1,2,4]triazino[1,2-a][1,2]diazepine-3,5(7H,13H)-dione

This compound was made by the same process used to make Example 1. 1HNMR (400 MHz, DMSO-d6) δ 7.62-7.54 (m, 2H), 7.37 (s, 1H), 7.33 (dd,J=8.3, 7.0 Hz, 2H), 7.30-7.09 (m, 6H), 6.39 (d, J=10.8 Hz, 1H), 4.44 (d,J=10.8 Hz, 1H), 4.00 (ddd, J=13.4, 8.8, 4.9 Hz, 1H), 3.31 (dt, J=10.9,5.0 Hz, 1H), 2.70 (dq, J=12.6, 3.7 Hz, 2H), 1.63-1.41 (m, 4H), 1.32-1.18(m, 1H), 1.14-1.00 (m, 1H). MS m/z 417.4 (M+1).

Example 7.13-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,10,11-tetrahydropyridazino[1′,6′:4,5][1,2,4]triazino[1,2-a][1,2]diazepine-3,5(7H,13H)-dione

This compound was made by the same process used to make Example 1. 1HNMR (400 MHz, DMSO-d6) δ 7.63-7.54 (m, 1H), 7.46-7.33 (m, 3H), 7.29-7.20(m, 2H), 7.15 (dt, J=7.8, 1.2 Hz, 1H), 7.11-7.03 (m, 1H), 7.03-6.94 (m,1H), 6.46 (d, J=10.9 Hz, 1H), 4.67 (d, J=10.9 Hz, 1H), 4.02 (ddd,J=13.3, 8.8, 4.8 Hz, 1H), 3.29 (dt, J=10.9, 5.0 Hz, 1H), 2.71 (dddd,J=18.7, 10.9, 7.1, 2.9 Hz, 2H), 1.66-1.41 (m, 4H), 1.26 (q, J=9.4, 8.9Hz, 1H), 1.15-1.00 (m, 1H). MS m/z 453.3 (M+1).

Example 8.(R)-12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-3H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5(12H)-dioneIntermediate 8.1.(R)-12-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,7,8,9,10-hexahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazin-4-yl(S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate and(S)-12-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,7,8,9,10-hexahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazin-4-yl(S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate

12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-3H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5(12H)-dione(127 mg, 0.290 mmol) was dissolved with stirring under N2 in dry THF(Volume: 4 mL) before the addition of TEA (0.081 mL, 0.579 mmol).(R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride (73.2 mg, 0.290mmol) was added dropwise. The reaction was stirred at room temperaturefor 90 minutes before being partitioned between EtOAc (10 mL) and water(10 mL). The phases were separated and the organic layer was washed withbrine, dried over Na₂SO₄ and concentrated. The residue was purified byISCO (24 g silica gel column, 0-100% EtOAc in heptane). Thediastereomers were then separated via chiral HPLC (IC column,heptanes/EtOH=80/20) to yield:

(R)-12-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,7,8,9,10-hexahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazin-4-yl(S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (63 mg, 0.096 mmol, 33%yield, 99% ee). ¹H NMR (400 MHz, Chloroform-d) δ 7.90 (d, J=7.5 Hz, 2H),7.62 (s, 1H), 7.54-7.29 (m, 4H), 7.19 (q, J=7.8 Hz, 1H), 7.07-6.81 (m,6H), 5.57 (d, J=10.2 Hz, 1H), 4.68-4.43 (m, 2H), 3.83 (s, 3H), 3.08 (d,J=10.5 Hz, 1H), 3.03-2.87 (m, 1H), 2.66 (t, J=11.5 Hz, 1H), 1.93-1.46(m, 4H). MS m/z 655.3 (M+1).

(S)-12-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,7,8,9,10-hexahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazin-4-yl(S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (57 mg, 0.087 mmol, 30%yield, 99% ee). 1H NMR (400 MHz, Chloroform-d) δ 7.94 (s, 2H), 7.64 (s,1H), 7.50-7.41 (m, 3H), 7.35 (q, J=7.5 Hz, 1H), 7.19 (q, J=7.6 Hz, 1H),7.02 (dd, J=14.8, 8.4 Hz, 3H), 6.96-6.88 (m, 2H), 6.85 (d, J=7.6 Hz,1H), 5.57 (d, J=9.9 Hz, 1H), 4.62 (s, 1H), 4.49 (s, 1H), 3.84 (s, 3H),3.09 (d, J=10.8 Hz, 1H), 2.93 (s, 1H), 2.66 (td, J=12.5, 3.3 Hz, 1H),1.82 (s, 2H), 1.58 (s, 1H), 1.27 (s, 1H). MS m/z 655.3 (M+1).

Example 8.(R)-12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-3H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5(12H)-dione

To a solution of(R)-12-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,7,8,9,10-hexahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazin-4-yl(S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (50 mg, 0.076 mmol)dissolved in MeOH (Volume: 382 μl, Ratio: 1.000) and H₂O (Volume: 382μl, Ratio: 1.000) was added LiOH.H₂O (32.1 mg, 0.764 mmol. The mixturewas stirred at rt for 1 h, then diluted with EtOAc, washed with 1N HCl,brine and dried over Na₂SO₄ filtered and concentrated. The crude waspurification by reverse-phase HPLC (MeCN/water with 0.1% TFA). Thefractions containing product were combined, frozen and lyophilized togive(R)-12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-3H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5(12H)-dione(3.7 mg, 0.006 mmol, 8.33% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.45 (d,J=10.1 Hz, 1H), 7.39-7.30 (m, 3H), 7.20 (ddd, J=24.4, 19.0, 9.8 Hz, 3H),7.09-6.92 (m, 2H), 6.39 (d, J=10.8 Hz, 1H), 4.80 (d, J=10.7 Hz, 1H),4.29 (d, J=11.9 Hz, 1H), 3.20 (d, J=9.7 Hz, 1H), 2.86 (t, J=11.1 Hz,1H), 2.43-2.27 (m, 1H), 1.72-1.33 (m, 4H). MS m/z 439.1 (M+1).

Example 9.(S)-12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione

This compound was made by the same process used to make Example 8. 1HNMR (400 MHz, DMSO-d6) δ 7.45 (d, J=11.7 Hz, 1H), 7.39-7.29 (m, 3H),7.29-7.11 (m, 3H), 7.08-6.92 (m, 2H), 6.39 (d, J=10.7 Hz, 1H), 4.80 (d,J=10.8 Hz, 1H), 4.29 (d, J=11.2 Hz, 1H), 3.20 (d, J=10.1 Hz, 1H), 2.86(t, J=11.1 Hz, 1H), 2.42-2.28 (m, 1H), 1.70-1.35 (m, 4H). MS m/z 439.1(M+1).

Example 10.(9aR,10S)-10-benzhydryl-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dioneIntermediate 10.1.(R)-2,2-diphenyl-1-((R)-1-tritylpyrrolidin-2-yl)ethan-1-ol and(S)-2,2-diphenyl-1-((R)-1-tritylpyrrolidin-2-yl)ethan-1-ol

To a solution of diphenylmethane (2.155 ml, 12.89 mmol) in THF (Volume:58.6 ml) at RT was added a solution of n-butyllithium (2.5 M in hexane)(4.69 ml, 11.71 mmol). After 10 minutes, the mixture was added asolution of (R)-1-tritylpyrrolidine-2-carbaldehyde (2 g, 5.86 mmol: seeJ. Am. Chem. Soc., 2008, 130, 7562-7563) in THF (6 mL). After 15minutes, the reaction mixture was quenched with saturated aqueous NH4 Cland extracted with EtOAc (twice). The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by ISCO (220 g silica gel column, 0-40%EtOAc in heptane) to give(R)-2,2-diphenyl-1-((R)-1-tritylpyrrolidin-2-yl)ethan-1-ol (1.64 g, 3.22mmol, 54.9% yield) (Peak 1) as a sticky white solid (1H NMR (400 MHz,Chloroform-d) δ 7.50-7.43 (m, 6H), 7.41-7.36 (m, 2H), 7.36-7.09 (m,17H), 5.90 (s, 1H), 3.96-3.79 (m, 2H), 3.62 (t, J=6.8 Hz, 1H), 3.18(ddd, J=12.9, 9.3, 6.9 Hz, 1H), 3.04 (ddd, J=13.3, 8.9, 4.9 Hz, 1H),1.45-1.35 (m, 1H), 0.76 (ddd, J=12.1, 8.9, 2.8 Hz, 1H), 0.65 (ddd,J=13.0, 5.9, 2.6 Hz, 1H), 0.59-0.46 (m, 1H)) and(S)-2,2-diphenyl-1-((R)-1-tritylpyrrolidin-2-yl)ethan-1-ol (0.62 g,1.216 mmol, 20.77% yield) (Peak 2) as a white solid (1H NMR (400 MHz,Chloroform-d) δ 7.41 (dt, J=6.2, 1.6 Hz, 6H), 7.30-7.01 (m, 17H),6.67-6.61 (m, 2H), 4.81 (dd, J=10.9, 2.4 Hz, 1H), 3.64 (d, J=10.9 Hz,1H), 3.32 (ddd, J=8.9, 6.8, 2.4 Hz, 1H), 3.16 (ddd, J=12.1, 10.4, 6.3Hz, 1H), 2.96 (ddd, J=11.6, 7.8, 2.5 Hz, 1H), 2.65 (s, 1H), 1.82 (dddd,J=12.4, 10.0, 8.0, 6.6 Hz, 1H), 1.23 (ddp, J=14.9, 8.8, 3.2 Hz, 1H),1.17-1.03 (m, 1H), −0.01-0.15 (m, 1H)).

Intermediate 10.2. (R)-2,2-diphenyl-1-((R)-pyrrolidin-2-yl)ethanol

Added HCl (3.0 M in water) (683 μl, 2.048 mmol) to a suspension of(R)-2,2-diphenyl-1-((R)-1-tritylpyrrolidin-2-yl)ethan-1-ol (348 mg,0.683 mmol) in MeOH (Volume: 6828 μl) at RT. The white suspensioneventually became clear and then later precipitate formed again. After 1hour, the mixture was then concentrated on the rotovap to give a yellowoil. Toluene was added and the mixture was concentrated again on therotovap again to an oily white solid. Used without further purification.MS m/z 268.2 (M+1).

Intermediate 10.3.1-benzyl-5-(benzyloxy)-3-((R)-2-((R)-1-hydroxy-2,2-diphenylethyl)pyrrolidine-1-carbonyl)pyridazin-4(1H)-one

To a solution of1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid(253 mg, 0.751 mmol) in DCM (4 ML) at RT was added Huenig's Base (477μl, 2.73 mmol) and HATU (338 mg, 0.888 mmol). Stirred at RT for 15 min,then added a solution of crude(R)-2,2-diphenyl-1-((R)-pyrrolidin-2-yl)ethanol (208 mg, 0.683 mmol) andHuenig's base (0.4 mL) in DCM (4 mL). The mixture was stirred at RT for1 h, diluted with DCM and washed with water and brine. The organic layerwas dried over Na₂SO₄, filtered and concentrated on the rotovap. Theresidue was purified by ISCO (40 g silica gel column, 5-100% EtOAc(containing 10% MeOH) in heptane) to give1-benzyl-5-(benzyloxy)-3-((R)-2-((R)-1-hydroxy-2,2-diphenylethyl)pyrrolidine-1-carbonyl)pyridazin-4(1H)-one(315 mg, 0.538 mmol, 79% yield) as an oil. MS m/z 586.4 (M+1).

Intermediate 10.4.(R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2,2-diphenylethylMethanesulfonate

To a solution of1-benzyl-5-(benzyloxy)-3-((R)-2-((R)-1-hydroxy-2,2-diphenylethyl)pyrrolidine-1-carbonyl)pyridazin-4(1H)-one(315 mg, 0.538 mmol) in pyridine (Volume: 5378 μl) at 0° C. was addedMsCl (168 μl, 2.151 mmol). The ice bath was removed and the mixturestirred at RT for 1 hour. Added another 100 uL of mesyl chloride.Stirred 30 minutes longer. The reaction mixture was diluted with DCM andwashed with water, then 0.5 N aqueous HCl (2 times), and water again.The organic layer was dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by ISCO (80 g silica gel column, 5-100%EtOAc (containing 10% MeOH) in heptane) to give(R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2,2-diphenylethylmethanesulfonate (120 mg, 0.181 mmol, 33.6% yield) as a yellow solid. MSm/z 664.3 (M+1).

Intermediate 10.5.(R)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2,2-diphenylethylMethanesulfonate

A solution of(R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2,2-diphenylethylmethanesulfonate (102 mg, 0.154 mmol) in MeOH (Volume: 5 mL) was purgedwith nitrogen. Added a spatula tip of 10% Pd/C (32.7 mg, 0.031 mmol) andattached a hydrogen balloon. The flask was evacuated and refilled withhydrogen (3 times) and then stirred vigorously at RT under a balloon ofhydrogen. After 30 min, the reaction was purged with nitrogen and thenfiltered through a plug of celite, using MeOH to wash through. Thefiltrate was concentrated in vacuo, azeotroped from toluene and usedwithout further purification. MS m/z 484.3 (M+1).

Example 10.(9aR,10S)-10-benzhydryl-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione

To a solution of crude(R)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2,2-diphenylethylmethanesulfonate (61.4 mg, 0.127 mmol) in DMF (Volume: 2 mL) at RT wasadded potassium carbonate (52.7 mg, 0.381 mmol). After overnight at RT,The reaction mixture was filtered through a 1 micron filter and purifiedin 2 batches directly on the reverse-phase prep HPLC (MeCN/H2O with 0.1%TFA eluent) to give(9aR,10S)-10-benzhydryl-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione(18 mg, 0.036 mmol, 28.0% yield) as a grey solid. 1H NMR (400 MHz,DMSO-d6) δ 7.63-7.57 (m, 2H), 7.38 (t, J=7.6 Hz, 2H), 7.29-7.23 (m, 1H),7.22 (s, 1H), 7.04 (td, J=4.9, 2.3 Hz, 3H), 6.95 (dd, J=7.6, 2.0 Hz,2H), 5.68 (dd, J=9.6, 3.6 Hz, 1H), 4.55 (d, J=9.5 Hz, 1H), 4.48 (ddd,J=10.1, 5.9, 4.0 Hz, 1H), 3.76-3.58 (m, 2H), 1.91 (tdd, J=9.5, 5.0, 3.0Hz, 1H), 1.82-1.63 (m, 2H), 1.51-1.40 (m, 1H). MS m/z 388.3 (M+1).

Example 11.(9aR,10R)-10-benzhydryl-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione

This compound was made by the same process used to make Example 10. 1HNMR (400 MHz, DMSO-d6) δ 7.45 (s, 1H), 7.37-7.32 (m, 2H), 7.32-7.17 (m,8H), 5.45 (dd, J=10.4, 6.1 Hz, 1H), 5.08 (d, J=6.1 Hz, 1H), 4.04 (td,J=10.5, 5.7 Hz, 1H), 3.55-3.42 (m, 2H), 1.89 (dt, J=12.6, 7.4 Hz, 1H),1.74-1.59 (m, 1H), 1.55-1.38 (m, 2H). MS m/z 388.3 (M+1).

Example 12.(9aS,10R)-10-benzhydryl-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione

This compound was made by the same process used to make Example 10. 1HNMR (400 MHz, DMSO-d6) δ 7.66-7.55 (m, 2H), 7.38 (t, J=7.6 Hz, 2H),7.29-7.23 (m, 1H), 7.21 (s, 1H), 7.08-7.01 (m, 3H), 6.96 (dd, J=7.6, 2.0Hz, 2H), 5.68 (dd, J=9.6, 3.6 Hz, 1H), 4.55 (d, J=9.6 Hz, 1H), 4.48(ddd, J=10.3, 6.1, 4.0 Hz, 1H), 3.78-3.68 (m, 1H), 3.62 (td, J=11.7,11.0, 7.2 Hz, 1H), 1.91 (tdd, J=9.1, 5.7, 1.7 Hz, 1H), 1.82-1.64 (m,2H), 1.53-1.37 (m, 1H). MS m/z 388.3 (M+1).

Example 13.(9aR,10R)-10-benzhydryl-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione

This compound was made by the same process used to make Example 10. 1HNMR (400 MHz, DMSO-d6) δ 7.45 (s, 1H), 7.37-7.32 (m, 2H), 7.29 (dd,J=5.8, 3.5 Hz, 6H), 7.21 (dtd, J=7.1, 4.5, 2.1 Hz, 2H), 5.45 (dd,J=10.4, 6.1 Hz, 1H), 5.08 (d, J=6.0 Hz, 1H), 4.04 (td, J=10.4, 5.6 Hz,1H), 3.61-3.52 (m, 1H), 3.46 (ddd, J=12.2, 10.0, 7.7 Hz, 1H), 1.96-1.84(m, 1H), 1.75-1.58 (m, 1H), 1.56-1.37 (m, 2H). MS m/z 388.3 (M+1).

Example 14.(9aR,10S)-10-((R)-(3-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dioneIntermediate 14.1. (R,E)-tert-butyl2-(3-fluorostyryl)pyrrolidine-1-carboxylate

To a solution of diethyl 3-fluorobenzylphosphonate (2.60 g, 10.54 mmol)in THF (Volume: 30 mL) at 0° C. was added a solution of LHMDS (1.0 M inTHF) (10.44 mL, 10.44 mmol) dropwise. The reaction mixture was stirredat 0° C. for 20 minutes, then added a solution of (R)-tert-butyl2-formylpyrrolidine-1-carboxylate (2 g, 10.04 mmol) in THF (10 mL)dropwise. The reaction mixture was slowly warm to RT in 1 h and thenstirred additional 1 h at RT. The reaction was quenched with water andextracted with EtOAc (twice). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by ISCO (80 g silica gel column, 0-40% EtOAc inheptane) to give (R,E)-tert-butyl2-(3-fluorostyryl)pyrrolidine-1-carboxylate (2.15 g, 7.23 mmol, 72.0%yield) as a white solid. MS m/z 292.0 (M+1).

Intermediate 14.2. (R)-tert-butyl2-((2S,3S)-3-(3-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and(R)-tert-butyl2-((2R,3R)-3-(3-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate

Added mCPBA (1327 mg, 7.69 mmol) to a solution of (R,E)-tert-butyl2-(3-fluorostyryl)pyrrolidine-1-carboxylate (640 mg, 2.197 mmol) in DCM(Volume: 20 mL) at RT. Reaction mixture was stirred at RT overnight. Thereaction was quenched with water and extracted with DCM. The combinedorganic extracts were washed with Sat. sodium thiosulfate, sodiumbicarbonate and brine. The organics was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by ISCO (40 g silica gelcolumn, 0-40% EtOAc in heptane) to give a mixture of (R)-tert-butyl2-((2S,3S)-3-(3-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and(R)-tert-butyl2-((2R,3R)-3-(3-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate (0.35g, 1.025 mmol, 46.7% yield). MS m/z 308.3 (M+1).

Intermediate 14.3. (R)-tert-butyl2-((1R,2R)-2-(3-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylateand (R)-tert-butyl 2-((1S,2S)-2-(3-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate

A mixture of (R)-tert-butyl2-((2S,3S)-3-(3-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and(R)-tert-butyl2-((2R,3R)-3-(3-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate (220mg, 0.716 mmol) and copper(I) bromide-dimethyl sulfide complex (169 mg,0.823 mmol) in THF (Volume: 4 mL) was cooled to between −20 and −30° C.in an acetone bath with periodic dry ice additions. A solution ofphenylmagnesium chloride (2.0 M in THF) (2.86 mL, 5.73 mmol) was addeddropwise. After 40 min at this temperature, the reaction mixture wasslowly warm to 0° C. in 30 min and kept at 0° C. for additional 60 min.The reaction was quenched with saturated aqueous NH₄Cl solution andextracted with EtOAc (2 times). The combined organic extracts were driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by ISCO (12 g silica gel column, 0-40% EtOAc in heptane) toyield (R)-tert-butyl2-((1R,2R)-2-(3-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate(40 mg, 0.104 mmol, 14.50% yield, ¹H NMR (400 MHz, CDCl₃) δ ppm 7.39 (d,J=7.73 Hz, 2H), 7.27-7.36 (m, 2H), 7.14-7.26 (m, 4H), 6.91 (td, J=8.84,2.62 Hz, 1H), 4.09-4.25 (m, 1H), 4.01 (d, J=2.89 Hz, 1H), 3.73-3.87 (m,1H), 3.50 (br d, J=4.84 Hz, 1H), 3.19-3.34 (m, 1H), 1.80-1.99 (m, 2H),1.68-1.80 (m, 2H), 1.37-1.49 (m, 9H)) and (R)-tert-butyl2-((1S,2S)-2-(3-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate(85 mg, 0.221 mmol, 30.8% yield, 1H NMR (400 MHz, CDCl3) δ ppm 7.31 (dt,J=14.71, 7.44 Hz, 4H), 7.06-7.25 (m, 4H), 6.77-6.96 (m, 1H), 4.96 (br d,J=10.03 Hz, 1H), 3.84 (d, J=10.32 Hz, 1H), 3.74 (br s, 1H), 3.55 (br s,1H), 3.20 (dt, J=10.66, 7.46 Hz, 1H), 2.00-2.20 (m, 1H), 1.72-1.93 (m,3H), 1.57-1.68 (m, 1H), 1.49 (s, 9H)). MS m/z 386.3 (M+1).

Intermediate 14.4. (R)-tert-butyl2-((1R,2R)-2-(3-fluorophenyl)-1-((methylsulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxylate

To a solution of (R)-tert-butyl2-((1R,2R)-2-(3-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate(85 mg, 0.221 mmol) in DCM (Volume: 2 mL) at 0° C. was added TEA (0.154mL, 1.103 mmol) and MsCl (0.052 mL, 0.662 mmol). After 10 min at thistemperature, the reaction mixture was took out from ice bath and stirred1H at RT. Additional MsCl (0.052 mL, 0.662 mmol) was added. Afteranother 2 h at rt, the reaction was diluted with DCM and washed withwater and brine. The DCM layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by ISCO (12 g silica gelcolumn, 0-50% EtOAc in heptane) to give (R)-tert-butyl2-((1R,2R)-2-(3-fluorophenyl)-1-((methylsulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxylate(10.2 mg, 0.022 mmol, 9.98% yield). MS m/z 464.2 (M+1).

Intermediate 14.5.(1R,2R)-2-(3-fluorophenyl)-2-phenyl-1-((R)-pyrrolidin-2-yl)ethylmethanesulfonate

Added HCl (1 mL, 4.0 mmol, 4.0 M in dioxane) to (R)-tert-butyl2-((1R,2R)-2-(3-fluorophenyl)-1-((methylsulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxylate(10.2 mg, 0.022 mmol) at RT. After 1H at RT, the mixture wasconcentrated in vacuo and proceed for next step. MS m/z 364.3 (M+1).

Intermediate 14.6.(1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(3-fluorophenyl)-2-phenylethylMethanesulfonate

Added Huenig's Base (0.019 mL, 0.110 mmol) and HATU (10.88 mg, 0.029mmol) to a solution of1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid(8.14 mg, 0.024 mmol) in DCM (Volume: 1 mL) at RT. After 15 min, themixture was added a solution of crude(1R,2R)-2-(3-fluorophenyl)-2-phenyl-1-((R)-pyrrolidin-2-yl)ethylmethanesulfonate (8 mg, 0.022 mmol) and Huenig's base (0.05 mL) in DCM(0.5 mL). The mixture was stirred at RT for 1 h, diluted with DCM andwashed with water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated on the rotovap. The residue was purified byISCO (4 g silica gel column, 0-100% EtOAc (containing 10% MeOH) inheptane) to give(1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(3-fluorophenyl)-2-phenylethylmethanesulfonate (14.2 mg, 0.021 mmol, 95% yield). MS m/z 682.1 (M+1).

Intermediate 14.7.(1R,2R)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-phenylethylMethanesulfonate

A solution of(1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(3-fluorophenyl)-2-phenylethylmethanesulfonate (14.5 mg, 0.021 mmol) in MeOH (Volume: 5 mL) was purgedwith nitrogen. Added a spatula tip of 10% Pd/C (4.53 mg, 4.25 μmol) andattached a hydrogen balloon. The flask was evacuated and refilled withhydrogen (3 times) and then stirred vigorously at RT under a balloon ofhydrogen. After 1H, the reaction mixture was filtered through celite,washed with MeOH. Filtered and evaporated. Proceed for next step withoutfurther purification. MS m/z 502.3 (M+1).

Example 14.(9aR,10S)-10-((R)-(3-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione

Added potassium carbonate (8.76 mg, 0.063 mmol) to a solution of crude(1R,2R)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-phenylethylmethanesulfonate (10.6 mg, 0.021 mmol) in DMF (Volume: 1 mL) at RT. Themixture was stirred at RT for 4H, filtered through a 1 micron filter andpurified in 2 batches directly on the reverse-phase prep HPLC (MeCN/H2Owith 0.1% TFA eluent). Fractions contains product were combined andlyophilyzed to give(9aR,10S)-10-((R)-(3-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione(3.9 mg, 7.36 μmol, 34.8% yield) as an off white solid. 1H NMR (400 MHz,DMSO-d6) δ 7.50 (d, J=10.5 Hz, 1H), 7.46-7.35 (m, 2H), 7.18 (s, 1H),7.11-6.99 (m, 4H), 6.97-6.90 (m, 2H), 5.70 (dd, J=9.6, 3.5 Hz, 1H), 4.60(d, J=9.6 Hz, 1H), 4.45 (dt, J=10.1, 5.5 Hz, 1H), 3.78-3.66 (m, 1H),3.66-3.53 (m, 1H), 1.91 (dt, J=12.6, 6.7 Hz, 1H), 1.85-1.60 (m, 2H),1.40 (qd, J=11.5, 6.9 Hz, 1H). MS m/z 406.2 (M+1).

Example 15.(9aR,10R)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione

This compound was made by the same process used to make Example 14. 1HNMR (400 MHz, MeOD) δ ppm 7.64 (s, 1H), 7.26-7.40 (m, 2H), 7.08-7.22 (m,3H), 6.94-7.07 (m, 3H), 5.40 (dd, J=10.78, 6.09 Hz, 1H), 5.15 (d, J=6.06Hz, 1H), 4.09 (td, J=10.51, 5.87 Hz, 1H), 3.67-3.77 (m, 1H), 3.53-3.65(m, 1H), 1.99-2.09 (m, 1H), 1.58-1.85 (m, 3H). MS m/z 424.3 (M+1).

Example 16.(9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione

This compound was made by the same process used to make Example 14. 1HNMR (400 MHz, MeOD) 5 ppm 7.29-7.52 (m, 4H), 7.01-7.12 (m, 2H),6.70-6.86 (m, 3H), 5.76 (dd, J=9.59, 3.62 Hz, 1H), 4.61 (d, J=9.63 Hz,1H), 4.51 (dt, J=10.20, 5.12 Hz, 1H), 3.82-3.93 (m, 1H), 3.67 (td,J=11.16, 7.56 Hz, 1H), 2.01-2.10 (m, 1H), 1.78-1.97 (m, 2H),1.54-1,67(m, 1H). MS m/z 424.3 (M+1).

Example 17.(9aS,10R)-10-((S)-(3-chlorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione

This compound was made by the same process used to make Example 14. ¹HNMR (400 MHz, DMSO-d6) δ 7.69 (t, J=1.9 Hz, 1H), 7.66-7.60 (m, 1H), 7.42(t, J=7.9 Hz, 1H), 7.36-7.29 (m, 1H), 7.22 (s, 1H), 7.12-7.00 (m, 3H),6.94 (dd, J=7.6, 1.9 Hz, 2H), 5.73 (dd, J=9.5, 3.6 Hz, 1H), 4.63 (d,J=9.5 Hz, 1H), 4.47 (ddd, J=10.2, 5.4, 3.4 Hz, 1H), 3.78-3.68 (m, 1H),3.62 (td, J=11.7, 11.0, 7.2 Hz, 1H), 2.01-1.89 (m, 1H), 1.87-1.78 (m,1H), 1.75-1.65 (m, 1H), 1.44 (qd, J=11.6, 6.8 Hz, 1H). MS m/z 422.3(M+1).

Example 18.(10aS)-11-benzhydryl-4-hydroxy-7,8,10a,11-tetrahydro-10H-pyridazino[1′,6′:4,5]pyrazino[2,1-c][1,4]oxazine-3,5-dione

This compound was made by the same process used to make Example 14except starting with tert-butyl (R)-3-formylmorpholine-4-carboxylate. 1HNMR (500 MHz, DMSO-d6) δ 7.58 (d, J=7.5 Hz, 2H), 7.39 (t, J=7.6 Hz, 2H),7.29 (t, J=7.3 Hz, 1H), 7.21 (d, J=6.6 Hz, 2H), 7.17 (s, 1H), 7.14 (q,J=6.1 Hz, 3H), 5.51 (d, J=11.2 Hz, 1H), 4.58 (d, J=11.1 Hz, 1H), 4.36(d, J=11.4 Hz, 1H), 3.98 (d, J=8.5 Hz, 1H), 3.75-3.67 (m, 4H), 3.04-2.95(m, 1H). MS m/z 404.3 (M+1).

Examples 19A and 19B

Intermediate 19.1.3-((tert-butyldimethylsilyl)oxy)-1,1-diphenylpropan-2-ol

To a solution of diphenylmethane (8.69 g, 51.6 mmol) in THF (258 mL) atRT under a nitrogen atmosphere was added a solution of n-butyllithium(2.5 M in hexanes, 19.6 mL, 49.0 mmol). The red solution stirred at RTfor 3 minutes, then 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (5.00,25.8 mmol) was added rapidly by syringe. The mixture was stirred foranother 5 minutes, then quenched with saturated aqueous NH4 Cl solutionand diluted with water. The mixture was extracted with EtOAc (twice) andthe combined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. Silica gel column chromatography(0-20% EtOAc in heptane) provided3-((tert-butyldimethylsilyl)oxy)-1,1-diphenylpropan-2-ol (4.7 g,colorless oil) in 53% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.42-7.37(m, 2H), 7.34-7.17 (m, 8H), 4.42 (ddd, J=9.3, 6.2, 3.5 Hz, 1H), 4.04 (d,J=9.0 Hz, 1H), 3.58 (dd, J=10.1, 3.4 Hz, 1H), 3.44 (dd, J=10.1, 6.2 Hz,1H), 2.51 (s, 1H), 0.90 (s, 9H), 0.03-0.01 (m, 6H).

Intermediate 19.2.3-((tert-butyldimethylsilyl)oxy)-1,1-diphenylpropan-2-ylmethanesulfonate

Methanesulfonyl chloride (1.4 mL, 17.8 mmol) was added dropwise to asolution of 3-((tert-butyldimethylsilyl)oxy)-1,1-diphenylpropan-2-ol(4.70 g, 13.7 mmol) and triethylamine (3.8 mL, 27.4 mmol) in DCM (137mL) at 0° C. The solution was stirred for 30 minutes, and then dilutedwith DCM and washed with water. The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo to give crude3-((tert-butyldimethylsilyl)oxy)-1,1-diphenylpropan-2-ylmethanesulfonate as a colorless oil. Used without further purification.MS m/z 421.4 (M+1).

Intermediate 19.3. 3-hydroxy-1,1-diphenylpropan-2-yl methanesulfonate

A solution of hydrogen chloride (4.0 M in dioxane, 5.2 mL, 20.6 mmol)was added to a solution of crude3-((tert-butyldimethylsilyl)oxy)-1,1-diphenylpropan-2-ylmethanesulfonate (5.8 g, 13.7 mmol) in methanol (137 mL) at RT. Themixture was stirred for 1 h, and then concentrated in vacuo. Silica gelcolumn chromatography (25-80% EtOAc in heptane) provided3-hydroxy-1,1-diphenylpropan-2-yl methanesulfonate (3.81 g, colorlessoil) in 91% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.45-7.38 (m, 2H),7.37-7.29 (m, 6H), 7.29-7.20 (m, 2H), 5.46 (ddd, J=10.2, 5.4, 2.6 Hz,1H), 4.33 (d, J=10.2 Hz, 1H), 3.87 (dd, J=12.9, 2.6 Hz, 1H), 3.68 (dd,J=12.9, 5.5 Hz, 1H), 2.37 (s, 3H).

Intermediate 19.4. 2-((methylsulfonyl)oxy)-3,3-diphenylpropyl5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylate

To a solution of5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylicacid (700 mg, 1.86 mmol) in DCM (6 ML) at 0° C. was added Huenig's Base(812 μl, 4.65 mmol) and HATU (848 mg, 2.23 mmol). Stirred for 15 min,then added a solution of 3-hydroxy-1,1-diphenylpropan-2-ylmethanesulfonate (854 mg, 2.79 mmol) in DCM (3 mL). The mixture wasstirred at RT overnight, diluted with DCM and washed with water. Theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.Silica gel column chromatography (5-80% EtOAc in heptane) provided2-((methylsulfonyl)oxy)-3,3-diphenylpropyl5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylate(878 mg, white foam) in 71% yield. MS m/z 665.2 (M+1).

Intermediate 19.5. 2-((methylsulfonyl)oxy)-3,3-diphenylpropyl5-hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylate

A solution of 2-((methylsulfonyl)oxy)-3,3-diphenylpropyl5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylate(1.0 g, 1.5 mmol) in methanol (40 mL) was purged with nitrogen. 10%palladium on carbon (160 mg, 0.15 mmol) was added and the flask wasevacuated and refilled with hydrogen from a balloon (3 times). Themixture was stirred vigorously under a hydrogen atmosphere for 30minutes. The flask was then purged with nitrogen and the mixture wasfiltered through a plug of celite, using methanol to wash the filtercake. The filtrated was concentrated in vacuo to give crude2-((methylsulfonyl)oxy)-3,3-diphenylpropyl5-hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylate,which was used without further purification. MS m/z 575.4 (M+1).

Intermediate 19.6. 2-((methylsulfonyl)oxy)-3,3-diphenylpropyl5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carboxylate

Trifluoroacetic acid (20 mL) was added to a solution of crude2-((methylsulfonyl)oxy)-3,3-diphenylpropyl5-hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylate(864 mg, 1.50 mmol) in DCM (5 mL) at RT. The mixture was stirred for 5 hand then concentrated in vacuo to give crude2-((methylsulfonyl)oxy)-3,3-diphenylpropyl5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carboxylate, which was usedwithout further purification. MS m/z 445.3 (M+1).

Intermediate 19.7.8-benzhydryl-4-(benzyloxy)-7,8-dihydropyridazino[6,1-c][1,4]oxazine-3,5-dione

Cesium carbonate (5.39 g, 16.5 mmol) was added to a solution of crude2-((methylsulfonyl)oxy)-3,3-diphenylpropyl5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (840 mg, 1.50 mmol)in DMF at RT. The mixture was then stirred at 45° C. for 3 h. Benzylbromide (1 mL) was then added and the mixture was stirred for anotherhour at 45° C. The mixture was then cooled to RT and filtered to removesolids. The filtrate was concentrated in vacuo and the residue waspurified in batches by reverse-phase prep HPLC (MeCN/H2O with 0.1% TFAeluent) to give, after lyophilization,8-benzhydryl-4-(benzyloxy)-7,8-dihydropyridazino[6,1-c][1,4]oxazine-3,5-dione(91 mg, white solid) in 11% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.61-7.07(m, 16H), 5.63 (ddd, J=11.7, 2.4, 1.3 Hz, 1H), 5.46 (d, J=11.3 Hz, 1H),5.33 (d, J=11.3 Hz, 1H), 4.92 (dd, J=12.1, 2.6 Hz, 1H), 4.40 (d, J=11.5Hz, 1H), 4.23 (dd, J=12.2, 1.3 Hz, 1H). MS m/z 439.2 (M+1).

Intermediate 19.8. Isopropyl4-(benzyloxy)-2-(3-hydroxy-1,1-diphenylpropan-2-yl)-5-oxo-2,5-dihydropyridazine-3-carboxylate

Titanium isopropoxide (0.11 mL, 0.37 mmol) was added to a suspension of8-benzhydryl-4-(benzyloxy)-7,8-dihydropyridazino[6,1-c][1,4]oxazine-3,5-dione(34 mg, 0.062 mmol) in 2-propanol (6 mL). The mixture was heated at 75°C. for 3 h and then cooled to RT. The mixture was diluted with EtOAc andbrine. The layers were separated and the aqueous layer was extractedwith EtOAc (twice) and the combined organic extracts were dried overNa₂SO₄, filtered and concentrated in vacuo to give a white residue. Theresidue was triturated with DCM and the DCM layer was pipetted off andconcentrated in vacuo to give a mixture of starting material and crudeisopropyl4-(benzyloxy)-2-(3-hydroxy-1,1-diphenylpropan-2-yl)-5-oxo-2,5-dihydropyridazine-3-carboxylate,which was used without further purification. MS m/z 499.3 (M+1).

Intermediate 19.9. Isopropyl4-(benzyloxy)-5-oxo-2-(3-oxo-1,1-diphenylpropan-2-yl)-2,5-dihydropyridazine-3-carboxylate

Dess-Martin periodinane (37 mg, 0.087 mmol) was added to a solution ofcrude isopropyl4-(benzyloxy)-2-(3-hydroxy-1,1-diphenylpropan-2-yl)-5-oxo-2,5-dihydropyridazine-3-carboxylatein DCM (1 mL) at RT. The mixture was stirred for 1 h, and then dilutedwith DCM and washed sequentially with saturated aqueous sodiumthiosulfate solution and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo to give crude isopropyl4-(benzyloxy)-5-oxo-2-(3-oxo-1,1-diphenylpropan-2-yl)-2,5-dihydropyridazine-3-carboxylate,which was used without further purification. MS m/z 497.2 (M+1).

Intermediate 19.12-benzhydryl-7-(benzyloxy)-3,4,12,12a-tetrahydro-2H-pyridazino[1′,6′:4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione

Methanol (2.4 mL, 60 mmol), 3-amino-1-propanol (1.8 mL, 24 mmol), andacetic acid (1.15 mL, 20.1 mmol) were carefully added to toluene (9 mL)at RT (exothermic). The mixture was agitated and 5 mL of the mixture wasremoved and added to crude isopropyl4-(benzyloxy)-5-oxo-2-(3-oxo-1,1-diphenylpropan-2-yl)-2,5-dihydropyridazine-3-carboxylate(0.1 g, 0.2 mmol) in a vial. The vial was capped and the mixture washeated at 85° C. for 5 h. The reaction was cooled to RT and diluted withEtOAc and water. The layers were separated and the aqueous layer wasextracted with EtOAc. The combined organic extracts were dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was taken up inDMSO and purified by reverse-phase prep HPLC (MeCN/water with 0.1% TFAeluent) to give two diastereomers of12-benzhydryl-7-(benzyloxy)-3,4,12,12a-tetrahydro-2H-pyridazino[1′,6′:4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione(white solid).

Diastereomer 1: LCMS Rt 0.91/1.50 min, m/z 494.2 (M+1). 1H NMR (400 MHz,DMSO-d6) δ 7.63-7.57 (m, 2H), 7.53-7.48 (m, 2H), 7.44-7.26 (m, 7H), 7.16(dd, J=6.7, 3.0 Hz, 2H), 7.09 (dd, J=5.0, 1.9 Hz, 3H), 5.45 (dd, J=11.4,1.3 Hz, 1H), 5.35 (d, J=11.2 Hz, 1H), 5.20 (d, J=11.1 Hz, 1H), 4.77 (d,J=1.4 Hz, 1H), 4.55-4.45 (m, 1H), 4.37 (d, J=11.3 Hz, 1H), 4.01 (dd,J=11.5, 4.7 Hz, 1H), 3.85-3.75 (m, 1H), 3.00 (td, J=12.8, 3.0 Hz, 1H),1.66 (ddd, J=17.0, 8.4, 4.7 Hz, 1H), 1.44 (d, J=13.6 Hz, 1H).Diastereomer 2: LCMS Rt 0.92/1.50 min, m/z 494.2 (M+1). 1H NMR (400 MHz,DMSO-d6) δ 7.70 (s, 1H), 7.51-7.44 (m, 4H), 7.40-7.28 (m, 5H), 7.27-7.20(m, 1H), 7.16-7.03 (m, 5H), 5.61 (dd, J=7.2, 3.3 Hz, 1H), 5.07 (d, J=3.3Hz, 1H), 4.96 (d, J=1.9 Hz, 2H), 4.88 (d, J=7.1 Hz, 1H), 4.26 (ddd,J=13.4, 5.1, 2.9 Hz, 1H), 3.94 (dd, J=11.1, 4.5 Hz, 1H), 3.45-3.39 (m,1H), 3.13 (ddd, J=13.2, 11.7, 4.0 Hz, 1H), 1.93-1.79 (m, 1H), 1.66 (dt,J=13.8, 3.4 Hz, 1H).

Examples 19A and 19B.12-benzhydryl-7-hydroxy-3,4,12,12a-tetrahydro-2H-pyridazino[1′,6′:4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione

Trifluoroacetic acid (5 mL) was added to crude12-benzhydryl-7-(benzyloxy)-3,4,12,12a-tetrahydro-2H-pyridazino[1′,6′:4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione(mixture of diastereomers) at RT and the mixture was stirred for 20minutes. The reaction was then concentrated in vacuo and the residue wastaken up in DMSO. Purified by reverse-phase prep HPLC (MeCN/H2O with0.1% TFA eluent) to give, after lyophilization the trifluoroacetatesalts of two diastereomers of12-benzhydryl-7-hydroxy-3,4,12,12a-tetrahydro-2H-pyridazino[1′,6′:4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione(white solid).

Example 19A. LCMS Rt 0.80/1.50 min, m/z 404.2 (M+1). 1H NMR (400 MHz,DMSO-d6) δ 7.62-7.57 (m, 2H), 7.42-7.25 (m, 7H), 7.13 (dd, J=4.9, 2.7Hz, 2H), 5.50 (dd, J=11.2, 1.2 Hz, 1H), 4.87 (d, J=1.3 Hz, 1H), 4.48(dd, J=11.9, 7.0 Hz, 2H), 4.04 (dd, J=11.4, 4.9 Hz, 1H), 3.91-3.79 (m,1H), 3.12 (td, J=12.8, 3.1 Hz, 1H), 1.64 (dt, J=12.8, 6.6 Hz, 1H),1.54-1.45 (m, 1H).

Example 19B. LCMS Rt 0.82/1.50 min, m/z 404.2 (M+1). 1H NMR (400 MHz,DMSO-d6) δ 7.53 (s, 1H), 7.50-7.44 (m, 2H), 7.38-7.02 (m, 8H), 5.64 (dd,J=7.0, 3.5 Hz, 1H), 5.11 (d, J=3.4 Hz, 1H), 4.90 (d, J=7.0 Hz, 1H), 4.28(qd, J=7.1, 6.0, 3.7 Hz, 1H), 3.98 (dd, J=11.2, 4.7 Hz, 1H), 3.43 (td,J=11.8, 2.4 Hz, 1H), 3.19 (td, J=12.9, 3.8 Hz, 1H), 1.93 (dddd, J=12.5,9.0, 7.1, 5.2 Hz, 1H), 1.68 (ddd, J=14.1, 4.0, 2.1 Hz, 1H).

Note that Examples 19A and 19B, and other example numbers that include Aor B, were separated and tested as individual isomers, and biologicalactivity is reported for each isolated isomer. However, since theabsolute stereochemistry of the two isomers has not been determined, thestructures shown for these Examples do not depict stereochemistry, sothe A and B structures look the same, but each represents a singlediastereomer.

TABLE 1a Compounds of the Preceding Examples. Example No. Structure Name1

12-benzhydryl-4-hydroxy-7,8,9,10- tetrahydro-12H-dipyridazino[1,2-a:1′,6′-d][1,2,4]triazine-3,5-dione 2

12-(bis(3-fluorophenyl)methyl)-4- hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′- d][1,2,4]triazine-3,5-dione 3

12-(bis(4-chlorophenyl)methyl)-4- hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′- d][1,2,4]triazine-3,5-dione 4

12-(bis(3-chlorophenyl)methyl)-4- hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′- d][1,2,4]triazine-3,5-dione 5

12-(bis(4-fluorophenyl)methyl)-4- hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′- d][1,2,4]triazine-3,5-dione 6

13-benzhydryl-4-hydroxy- 8,9,10,11-tetrahydro-7H,13H-pyridazino[1′,6′:4,5][1,2,4]triazino [1,2-a][1,2]diazepine-3,5-dione 7

13-(bis(3-fluorophenyl)methyl)-4- hydroxy-8,9,10,11-tetrahydro- 7H,13H-pyridazino[1′,6′:4,5][1,2,4]triazino [1,2-a][1,2]diazepine-3,5-dione 8

(R)-12-(bis(3-fluorophenyl)methyl)- 4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′- d][1,2,4]triazine-3,5-dione 9

(S)-12-(bis(3-fluorophenyl)methyl)- 4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1′,6′- d][1,2,4]triazine-3,5-dione 10 

(9aR,10S)-10-benzhydryl-4- hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2- b]pyridazine-3,5-dione 11 

(9aR,10R)-10-benzhydryl-4- hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2- b]pyridazine-3,5-dione 12 

(9aS,10R)-10-benzhydryl-4- hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2- b]pyridazine-3,5-dione 13 

(9aS,10S)-10-benzhydryl-4- hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2- b]pyridazine-3,5-dione 14 

(9aR,10S)-10-((R)-(3- fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H- pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione 15 

(9aR,10R)-10-(bis(3- fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H- pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione 16 

(9aR,10S)-10-(bis(3- fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H- pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione 17 

(9aS,10R)-10-((S)-(3- chlorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H- pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione 18 

(10aS,11R)-11-benzhydryl-4- hydroxy-7,8,10a,11-tetrahydro- 10H-pyridazino[1′,6′:4,5]pyrazino[2,1- c][1,4]oxazine-3,5-dione    19A 

12-benzhydryl-7-hydroxy- 3,4,12,12a-tetrahydro-2H-pyridazino[1′,6′:4,5]pyrazino[2,1- b][1,3]oxazine-6,8-dione  19B

12-benzhydryl-7-hydroxy- 3,4,12,12a-tetrahydro-2H-pyridazino[1′,6′:4,5]pyrazino[2,1- b][1,3]oxazine-6,8-dione

TABLE 1b Additional examples made by the method of Example 1. 20

425.2 (400 MHz, DMSO-d6) δ 7.49 (dt, J = 10.8, 1.9 Hz, 1H), 7.39-7.31(m, 2H), 7.22-7.10 (m, 2H), 7.05 (dd, J = 10.0, 5.1 Hz, 2H), 6.95 (td, J= 8.6, 2.5 Hz, 1H), 6.75 (d, J = 10.2 Hz, 1H), 4.91 (d, J = 10.2 Hz,1H), 4.03 (dt, J = 11.5, 6.7 Hz, 1H), 3.15-3.01 (m, 2H), 2.83 (q, J =8.2 Hz, 1H), 2.04-1.85 (m, 3H) 21

417.2 (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.31-7.11 (m, 8H), 7.10-7.01(m, 2H), 6.30 (s, 1H), 3.88 (dd, J = 12.7, 4.6 Hz, 1H), 3.56 (d, J =11.1 Hz, 1H), 2.89 (td, J = 11.5, 2.8 Hz, 1H), 2.66 (td, J = 12.7, 3.2Hz, 1H), 1.81 (t, J = 12.6 Hz, 1H), 1.72 (d, J = 12.0 Hz, 1H), 1.61 (s,4H), 1.44-1.24 (m, 1H) 22

439.1 (400 MHz, DMSO-d6) δ 7.58-7.50 (m, 2H), 7.39-7.29 (m, 3H),7.19-7.08 (m, 2H), 7.05-6.96 (m, 2H), 6.32 (d, J = 10.7 Hz, 1H), 4.73(d, J = 10.7 Hz, 1H), 4.34-4.22 (m, 2H), 3.27-3.10 (m, 1H), 2.85 (dd, J= 12.1, 9.4 Hz, 1H), 2.41- 2.29 (m, 1H), 1.64 (d, J = 12.0 Hz, 1H),1.59-1.33 (m, 3H)    23A

417.1 (400 MHz, DMSO-d6) δ 7.55-7.46 (m, 2H), 7.34 (s, 1H), 7.30 (dt, J= 7.6, 4.1 Hz, 4H), 7.26-7.06 (m, 4H), 6.45 (d, J = 10.5 Hz, 1H), 4.57(d, J = 10.5 Hz, 1H), 4.36-4.23 (m, 1H), 3.68 (m, 1H), 2.42-2.26 (m,2H), 1.71-1.47 (m, 2H), 1.39 (t, J = 12.9 Hz, 2H), 0.69 (d, J = 6.5 Hz,3H)   23B

417.1 (400 MHz, DMSO-d6) δ 7.57-7.50 (m, 2H), 7.40-7.28 (m, 5H), 7.21(t, J = 7.3 Hz, 1H), 7.18-7.06 (m, 3H), 6.16 (d, J = 10.6 Hz, 1H), 4.66(d, J = 10.6 Hz, 1H), 4.32 (dt, J = 12.8, 3.3 Hz, 1H), 2.91 (ddt, J =12.4, 6.2, 3.1 Hz, 1H), 2.39 (ddd, J = 15.8, 8.3, 5.7 Hz, 1H), 1.70-1.59 (m, 1H), 1.54 (d, J = 9.3 Hz, 2H), 1.21-1.03 (m, 4H) 24

417.3 (400 MHz, DMSO-d6) δ 7.53-7.47 (m, 2H), 7.34-7.19 (m, 5H), 7.10(dp, J = 30.0, 7.0 Hz, 5H), 6.34 (d, J = 11.1 Hz, 1H), 4.68-4.57 (m,1H), 4.51 (d, J = 11.1 Hz, 1H), 3.35-3.13 (m, 1H), 2.80 (td, J = 11.1,3.2 Hz, 1H), 1.71 (d, J = 9.8 Hz, 1H), 1.57 (tt, J = 12.8, 4.8 Hz, 1H),1.43 (dt, J = 13.1, 3.4 Hz, 1H), 1.31 (d, J = 13.0 Hz, 1H), 0.57 (d, J =6.8 Hz, 3H)    25A

431.4 (400 MHz, DMSO-d6) δ 7.58-7.47 (m, 2H), 7.38-7.27 (m, 2H), 7.25(s, 1H), 7.22-7.05 (m, 6H), 6.52 (d, J = 11.2 Hz, 1H), 4.62-4.41 (m,4H), 3.73 (q, J = 5.7 Hz, 2H), 1.95-1.67 (m, 2H), 1.33- 1.02 (m, 2H),0.69 (dd, J = 6.6, 4.3 Hz, 6H)   25B

431.4 (400 MHz, DMSO-d6) δ 7.59-7.52 (m, 2H), 7.43-7.37 (m, 2H),7.36-7.27 (m, 3H), 7.23-7.09 (m, 4H), 6.08 (d, J = 10.4 Hz, 1H), 4.75(d, J = 10.3 Hz, 1H), 2.86 (ddd, J = 11.2, 6.1, 2.6 Hz, 1H), 2.77-2.63(m, 1H), 1.73 (s, 1H), 1.66 (ddd, J = 14.3, 9.0, 4.0 Hz, 1H), 1.57 (d, J= 7.1 Hz, 4H), 1.26-1.11 (m, 1H), 1.06 (d, J = 6.1 Hz, 3H)    26A

447.1 (400 MHz, DMSO-d6) δ 7.43 (s, 1H), 7.34-7.12 (m, 4H), 7.08-7.00(m, 2H), 6.75 (d, J = 7.7 Hz, 1H), 6.22 (d, J = 9.8 Hz, 1H), 4.80 (d, J= 15.0 Hz, 1H), 4.64 (d, J = 9.9 Hz, 1H), 4.22 (d, J = 12.4 Hz, 1H),3.90 (dd, J = 15.4, 10.5 Hz, 1H), 3.30 (d, J = 11.0 Hz, 1H), 2.82 (t, J= 10.5 Hz, 1H), 2.18-2.00 (m, 2H), 1.67- 1.55 (m, 2H), 1.45 (d, J = 14.7Hz, 4H)   26B

447.1 (400 MHz, DMSO-d6) δ 7.32-7.21 (m, 3H), 7.16 (q, J = 7.4, 6.8 Hz,3H), 6.95 (td, J = 7.3, 2.1 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.45 (d,J = 10.5 Hz, 1H), 4.93 (d, J = 15.6 Hz, 1H), 4.66 (t, J = 10.3 Hz, 1H),4.49-4.39 (m, 1H), 3.90 (dd, J = 15.3, 10.4 Hz, 3H), 3.11 (d, J = 11.7Hz, 1H), 2.92-2.76 (m, 2H), 1.61 (d, J = 8.2 Hz, 2H), 1.48 (t, J = 9.2Hz, 3H)    27A

431.4 (400 MHz, DMSO-d6) δ 7.32-7.25 (m, 4H), 7.21-7.12 (m, 2H), 6.94(d, J = 7.9 Hz, 1H), 6.77-6.66 (m, 2H), 5.94 (d, J = 10.0 Hz, 1H), 5.70(d, J = 15.2 Hz, 1H), 4.96 (d, J = 15.2 Hz, 1H), 4.50 (dd, J = 12.2, 8.4Hz, 3H), 3.04 (d, J = 11.1 Hz, 1H), 2.94-2.75 (m, 2H), 1.72- 1.39 (m,4H)   27B

431.4 (400 MHz, DMSO-d6) δ 7.27 (ddd, J = 7.5, 5.0, 2.6 Hz, 2H), 7.23(s, 1H), 7.20- 7.14 (m, 1H), 7.07 (dd, J = 19.1, 7.7 Hz, 3H), 6.95 (td,J = 7.5, 1.5 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.00 (d, J = 10.0 Hz,1H), 5.69 (d, J = 15.3 Hz, 1H), 4.95 (d, J = 15.3 Hz, 1H), 4.54-4.39 (m,3H)    28A

483.1 (400 MHz, DMSO-d6) δ 7.41 (s, 1H), 7.32 (td, J = 7.2, 3.1 Hz, 2H),7.27- 7.17 (m, 2H), 7.09 (q, J = 8.8 Hz, 1H), 6.76 (t, J = 7.1 Hz, 1H),6.52 (d, J = 10.4 Hz, 1H), 4.89-4.70 (m, 2H), 4.39 (d, J = 12.5 Hz, 1H),4.05 (d, J = 16.5 Hz, 1H), 3.08 (d, J = 10.9 Hz, 1H), 2.87 (t, J = 10.2Hz, 1H), 2.67-2.52 (m, 2H), 1.68-1.54 (m, 2H), 1.46 (s, 2H)   28B

483.1 (400 MHz, DMSO-d6) δ 7.42 (s, 1H), 7.32 (q, J = 8.9 Hz, 1H), 7.19(dd, J = 8.9, 5.0 Hz, 1H), 7.14-7.03 (m, 2H), 6.88 (td, J = 7.3, 6.9,1.9 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 6.27 (d, J = 9.8 Hz, 1H), 4.82(d, J = 9.8 Hz, 1H), 4.64 (dd, J = 15.8, 2.2 Hz, 1H), 4.30-4.20 (m, 1H),4.09 (d, J = 15.8 Hz, 1H), 3.28 (d, J = 11.7 Hz, 1H), 2.88-2.75 (m, 1H),2.33- 2.17 (m, 1H), 1.67-1.34 (m, 4H)

TABLE 1c Additional compounds prepared by the method of Examples 8-9.Example Mass No. Structure M + H 1H NMR 29

403.1 (400 MHz, DMSO-d6) δ 7.49 (d, J = 7.3 Hz, 2H), 7.36-7.23 (m, 5H),7.22- 7.05 (m, 4H), 6.32 (d, J = 10.6 Hz, 1H), 4.60 (d, J = 10.5 Hz,1H), 4.35-4.23 (m, 1H), 3.23 (d, J = 10.9 Hz, 2H), 2.84 (td, J = 10.9,2.6 Hz, 1H), 2.40 (td, J = 12.4, 2.8 Hz, 1H), 1.64 (d, J = 11.7 Hz, 1H),1.60-1.33 (m, 3H) 30

439.4 (400 MHz, DMSO-d6) δ 7.58-7.50 (m, 2H), 7.39-7.29 (m, 3H), 7.13(t, J = 8.9 Hz, 2H), 7.01 (t, J = 8.8 Hz, 2H), 6.32 (d, J = 10.7 Hz,1H), 4.73 (d, J = 10.7 Hz, 1H), 4.40-4.13 (m, 1H), 3.20 (d, J = 10.5 Hz,2H), 2.85 (dd, J = 12.3, 9.4 Hz, 1H), 2.45-2.29 (m, 1H), 1.64 (d, J =11.7 Hz, 1H), 1.49 (dt, J = 37.6, 12.3 Hz, 3H) 31

439.4 (400 MHz, DMSO-d6) δ 7.54 (dd, J = 8.6, 5.6 Hz, 2H), 7.40-7.29 (m,3H), 7.13 (t, J = 8.8 Hz, 2H), 7.01 (t, J = 8.8 Hz, 2H), 6.32 (d, J =10.7 Hz, 1H), 4.73 (d, J = 10.7 Hz, 1H), 4.29 (dd, J = 11.9, 3.5 Hz,1H), 3.20 (d, J = 10.8 Hz, 2H), 2.85 (dd, J = 12.3, 9.4 Hz, 1H), 2.45-2.28 (m, 1H), 1.64 (d, J = 12.2 Hz, 1H), 1.59-1.37 (m, 3H)

General Synthesis of Chiral N-Boc Amino Alcohols

Step G-1: tert-butyl (R,E)-2-(2-fluorostyryl)pyrrolidine-1-carboxylate

Added a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 36.5mL, 36.5 mmol) dropwise to a solution of diethyl2-fluorobenzylphosphonate (9.08 g, 36.9 mmol) in THF (80 mL) at 0° C.Stirred at 0° C. for 20 minutes, then added a solution of (R)-tert-butyl2-formylpyrrolidine-1-carboxylate (7 g, 35.1 mmol) in THF (30 mL)dropwise. Reaction mixture was stirred in ice bath for 1 h and thenslowly warmed to RT over 1 h and then stirred for an additional 1 h atRT. The reaction was quenched with water and extracted with EtOAc(twice). The combined organic extracts were washed with brine, driedover Na₂SO₄, filtered and concentrated. Silica gel column chromatography(EtOAc/heptane) provided tert-butyl(R,E)-2-(2-fluorostyryl)pyrrolidine-1-carboxylate (6.5 g, white solid)in 64% yield. MS m/z 236.3 (M-tBu+H).

Step G-2: tert-butyl(R)-2-((2S,3S)-3-(2-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylateand tert-butyl(R)-2-((2R,3R)-3-(2-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate

To tert-butyl (R,E)-2-(2-fluorostyryl)pyrrolidine-1-carboxylate (1.85 g,6.35 mmol) in DCM (60 mL) was added mCPBA (7.83 g, 31.7 mmol). Thereaction mixture was stirred at RT for 2H. The reaction was quenchedwith water and extracted with DCM (twice). The combined organic extractswere washed sequentially with saturated aqueous Na₂S₂O₃, saturatedaqueous NaHCO₃ and brine. The organic layer was then dried over Na₂SO₄,filtered and concentrated. Silica gel column chromatography(EtOAc/heptane) provided an inseparable mixture of tert-butyl(R)-2-((2S,3S)-3-(2-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylateand tert-butyl(R)-2-((2R,3R)-3-(2-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate(1.6 g, colorless oil) in 41% yield. The mixture was used in the nextstep without further purification.

Step G-3: tert-butyl(R)-2-((1R,2R)-2-(2-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylateand tert-butyl (R)-2-((1S,2S)-2-(2-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate

Added copper(I) bromide-dimethyl sulfide complex (0.495 g, 2.408 mmol)to a mixture of tert-butyl(R)-2-((2S,3S)-3-(2-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylateand tert-butyl(R)-2-((2R,3R)-3-(2-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate(0.74 g, 2.41 mmol) in THF (30 mL) at RT. Cooled to between −20 and −30°C. in an acetone bath with periodic dry ice additions. A solution ofphenylmagnesium bromide (1.0 M in THF, 9.63 mL, 9.63 mmol) was addeddropwise. Stirred 15 min and allowed the temperature to warm to 0° C.Added 2 equiv more of phenylmagnesium bromide and stirred another 20min. Added another 2 equiv of phenylmagnesium bromide and stirredanother 20 min. The reaction was quenched with saturated aqueous NH₄Clsolution and extracted with EtOAc (2 times). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated. Silica gelcolumn chromatography (EtOAc/heptane) provided tert-butyl(R)-2-((1R,2R)-2-(2-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate(353 mg, colorless oil, eluted first) in 38% yield and tert-butyl(R)-2-((1S,2S)-2-(2-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate(300 mg, white foam, eluted second) in 32% yield. MS m/z 286.2(MH-r-Boc).

Example 32.(9aR,10S)-10-((R)-(2-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Step 1: Tert-butyl(R)-2-((1R,2R)-2-(2-fluorophenyl)-1-((methylsulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl(R)-2-((1R,2R)-2-(2-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate(470 mg, 0.914 mmol) in pyridine (9 mL) at 0° C. was addedmethanesulfonyl chloride (1.069 mL, 13.72 mmol). After 5 min the icebath was removed and the reaction was stirred for 2 h at RT. Thereaction mixture was then partitioned between DCM and water. The DCMlayer was separated and washed with saturated aqueous NaHCO₃, thenbrine, dried over Na₂SO₄, filtered and concentrated. Silica gel columnchromatography (EtOAc/heptane) provided tert-butyl(R)-2-((1R,2R)-2-(2-fluorophenyl)-1-((methylsulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxylate(350 mg, white foam) in 83% yield. MS m/z 408.4 (MH⁺-tBu).

Step 2: (1R,2R)-2-(2-fluorophenyl)-2-phenyl-1-((R)-pyrrolidin-2-yl)ethylMethanesulfonate Hydrochloride

Added HCl (4.0 M in dioxane, 5 ml, 20 mmol) to tert-butyl(R)-2-((1R,2R)-2-(2-fluorophenyl)-1-((methylsulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxylate(350 mg, 0.755 mmol). Stirred for 1 h at RT. The reaction was thenconcentrated to give(1R,2R)-2-(2-fluorophenyl)-2-phenyl-1-((R)-pyrrolidin-2-yl)ethylmethanesulfonate hydrochloride, which was used in the next step withoutfurther purification. MS m/z 364.5 (MH⁺).

Step 3:(1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(2-fluorophenyl)-2-phenylethylMethanesulfonate

Added Huenig's Base (0.519 mL, 2.97 mmol) and HATU (367 mg, 0.966 mmol)to a solution of1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid(275 mg, 0.817 mmol) in DCM (6 mL) at RT. Stirred at RT for 15 min, thenadded a solution of crude(1R,2R)-2-(2-fluorophenyl)-2-phenyl-1-((R)-pyrrolidin-2-yl)ethylmethanesulfonate hydrochloride (270 mg, 0.743 mmol) in DCM (4 mL) and 2equiv of Huenig's base. The mixture was stirred at RT for 1H. Thereaction was then diluted with DCM and washed with water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Silicagel column chromatography (EtOAc/EtOH/heptane) provided(1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(2-fluorophenyl)-2-phenylethylmethanesulfonate (470 mg) in 93% yield. MS m/z 682.5 (MH⁺).

Step 4:(1R,2R)-2-(2-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-phenylethylmethanesulfonate

A solution of(1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(2-fluorophenyl)-2-phenylethylmethanesulfonate (470 mg, 0.689 mmol) in methanol (12 mL) was purgedwith nitrogen. Added 10% palladium on carbon (220 mg, 0.207 mmol) andattached a hydrogen balloon. The flask was evacuated and refilled withhydrogen (3 times) and then stirred vigorously for 6 h at RT under aballoon of hydrogen. The reaction mixture was filtered through celiteand the filter cake was washed with MeOH. The filtrate was concentratedto provide crude(1R,2R)-2-(2-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-phenylethylmethanesulfonate which was used in the next step without furtherpurification. MS m/z 502.4 (MH⁺).

Step 5:(9aR,10S)-10-((R)-(2-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

To a solution of crude(1R,2R)-2-(2-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-phenylethylmethanesulfonate (345 mg, 0.619 mmol) in DMF (10 mL) was added potassiumcarbonate (342 mg, 2.476 mmol) and the mixture was stirred overnight atRT. The reaction was filtered through a 1 micron filter and purified byreverse phase HPLC. Product fractions were combined, frozen andlyophilized to afford a formate salt of(9aR,10S)-10-((R)-(2-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione(125 mg, 0.275 mmol, white solid) in 44% yield over two steps. ¹H NMR(400 MHz, CD₃OD) δ ppm 7.91 (td, J=7.36, 2.01 Hz, 1H) 7.26-7.42 (m, 3H)7.02-7.17 (m, 4H) 6.96 (dd, J=6.38, 2.96 Hz, 2H) 5.79 (dd, J=9.56, 3.59Hz, 1H) 4.69 (d, J=9.63 Hz, 1H) 4.52 (dt, J=9.96, 5.12 Hz, 1H) 3.84-3.99(m, 1H) 3.57-3.73 (m, 1H) 2.01-2.12 (m, 1H) 1.91-2.00 (m, 1H) 1.78-1.91(m, 1H) 1.55 (qd, J=11.56, 6.80 Hz, 1H). MS m/z 406.4 (MH⁺).

TABLE 1d Additional compounds prepared by the method of Example 32.Example Mass No. Structure M + H 1H NMR 33

442.4 (400 MHz, MeOD) δ ppm 7.84-7.96 (m, 1 H) 7.46 (s, 1 H) 7.29-7.43(m, 2H) 7.08- 7.20 (m, 1 H) 6.90-7.06 (m, 2H) 6.78 (br d, J = 8.46 Hz, 1H) 5.81 (dd, J = 9.95, 3.64 Hz, 1 H) 4.72 (d, J = 9.98 Hz, 1 H) 4.52(dt, J = 10.12, 5.11 Hz, 1 H) 3.82-3.96 (m, 1 H) 3.63 (td, J = 11.20,7.43 Hz, 1 H) 1.98-2.09 (m, 1 H) 1.75-1.97 (m, 2H) 1.47 (qd, J = 11.61,6.70 Hz, 1 H) 34

442.3 (400 MHz, MeOD) δ ppm 1.47-1.62 (m, 1 H) 1.74-1.95 (m, 2H)2.00-2.11 (m, 1 H) 3.67 (td, J = 11.08, 7.38 Hz, 1 H) 3.80- 3.96 (m, 1H)4.44-4.55 (m, 1 H) 4.62 (d, J = 9.83 Hz, 1 H) 5.76 (dd, J = 9.83, 3.57Hz, 1 H) 6.70-6.84 (m, 1 H) 6.90-7.02 (m, 2 H) 7.03-7.11 (m, 1 H)7.33-7.53 (m, 4 H) 35

424.2 (400 MHz, MeOD) δ ppm 7.84-7.94 (m, 1 H) 7.28-7.44 (m, 3 H)7.07-7.17 (m, 1 H) 7.01 (dd, J = 8.58, 5.31 Hz, 2H) 6.82 (t, J = 8.71Hz, 2H)5.79 (dd, J = 9.78, 3.57 Hz, 1 H) 4.70 (d, J = 9.78 Hz, 1 H) 4.52(dt, J = 10.20, 4.98 Hz, 1 H) 3.81-3.96 (m, 1 H) 3.63 (td, J = 11.19,7.31 Hz, 1 H) 2.00- 2.10 (m, 1 H) 1.77-1.99 (m, 2H) 1.51 (qd, J = 11.52,6.63 Hz, 1 H) 36

442.5 (400 MHz, MeOD) δ ppm 1.54 (qd, J = 11.62, 7.14 Hz, 1 H) 1.73-1.93(m, 2H) 1.99-2.11 (m, 1 H) 3.67 (td, J = 11.08, 7.53 Hz, 1 H) 3.81-3.94(m, 1 H) 4.45-4.57 (m, 1 H) 4.66 (d, J = 9.88 Hz, 1 H) 5.78 (dd, J =9.85, 3.55 Hz, 1 H) 6.57-6.79 (m, 3 H) 7.06-7.16 (m, 1 H) 7.35-7.54(m, 4H) 37

438.3 (400 MHz, MeOD) δ ppm 1.56 (qd, J = 11.84, 6.46 Hz, 1 H) 1.76-2.11(m, 3 H) 2.13-2.40 (m, 3 H) 3.66 (td, J = 11.33, 7.36 Hz, 1 H) 3.82-3.99(m, 1 H) 4.48-4.65 (m, 1 H) 5.88 (br s, 1 H) 6.60-6.82 (m, 2 H)6.95-7.12 (m, 1 H) 7.21 (br s, 1 H) 7.30-7.45 (m, 3 H) 38

424.4 (400 MHz, MeOD) δ ppm 7.56 (d, J = 7.58 Hz, 2 H) 7.37-7.48 (m, 3H) 7.26-7.36 (m, 1 H) 6.85-7.05 (m, 2 H) 6.77 (dt, J = 4.36, 2.05 Hz, 1H) 5.76 (dd, J = 9.93, 3.62 Hz, 1 H) 4.45-4.64 (m, 2H) 3.87 (br dd, J =12.86, 7.83 Hz, 1 H) 3.58-3.72 (m, 1 H) 1.94-2.10 (m, 1 H) 1.70-1.91 (m,2 H) 1.46-1.64 (m, 1 H) 39

424.4 (400 MHz, MeOD) δ ppm 7.82-7.99 (m, 1 H) 7.26-7.47 (m, 3 H)7.01-7.20 (m, 2H) 6.69-6.92 (m, 3 H) 5.81 (dd, J = 9.78, 3.57 Hz, 1H)4.73 (d, J = 9.78 Hz, 1 H) 4.52 (dt, J = 10.04, 5.08 Hz, 1 H) 3.82-3.93(m, 1 H) 3.64 (td, J = 11.16, 7.36 Hz, 1 H) 2.01- 2.10 (m, 1 H)1.76-1.99(m, 2 H) 1.51 (qd, J = 11.53, 6.63 Hz, 1 H) 40

442.4 (400 MHz, MeOD) δ ppm 7.81-7.96 (m, 1 H) 7.45 (s, 1 H) 7.31-7.44(m, 2H) 7.06- 7.21 (m, 1 H) 6.52-6.79 (m, 3 H) 5.83 (dd, J = 9.98, 3.62Hz, 1 H) 4.75 (d, J = 9.98 Hz, 1 H) 4.52 (dt, J = 10.36, 4.97 Hz, 1 H)3.81-3.95 (m, 1 H) 3.63 (td, J = 11.21, 7.36 Hz, 1 H) 1.98-2.08 (m, 1 H)1.89-1.97 (m, 1 H) 1.73-1.88 (m, 1 H) 1.47 (qd, J = 11.59, 6.70 Hz, 1 H)41

438.4 1H NMR (400 MHz, MeOD) δ ppm 7.88- 7.99 (m, 1 H) 7.40 (s, 1 H)7.27-7.37 (m, 2H) 7.24 (br s, 1 H) 7.05-7.14 (m, 1 H) 6.61-6.78 (m, 2H)5.89 (br d, J = 9.05 Hz, 1 H) 5.02 (br d, J = 10.17 Hz, 1 H) 4.51- 4.61(m, 1 H)3.84-3.98 (m, 1 H) 3.60 (td, J = 11.25, 7.34 Hz, 1 H) 2.23 (s, 3H) 2.00- 2.07 (m, 1 H) 1.94(dt, J = 11.99, 5.91 Hz, 1 H) 1.77-1.89 (m, 1H) 1.36-1.54 (m, 1 H) 42

438.4 (400 MHz, MeOD) δ ppm 7.83-7.96 (m, 1 H) 7.24-7.44 (m, 3 H)6.98-7.15 (m, 2H) 6.93 (dd, J = 7.65, 1.30 Hz, 1 H) 6.57-6.77 (m, 2H)5.71(dd, J = 10.05, 3.59 Hz, 1 H) 5.46 (d, J = 10.03 Hz, 1 H) 4.49 (brdd, J = 10.07, 5.04 Hz, 1 H) 3.87-3.98 (m, 1 H) 3.54-3.69 (m, 4 H)2.01-2.12 (m, 1 H) 1.80-1.96 (m, 2H) 1.44-1.60 (m, 1 H) 43

420.4 (400 MHz, MeOD) δppm 7.88-8.04 (m, 1 H) 7.29-7.41 (m, 3 H) 7.22(br d, J = 6.60 Hz, 1 H) 7.02-7.12 (m, 1 H) 6.87-7.02 (m, 3 H) 5.90 (brd, J = 7.63 Hz, 1 H) 5.06 (br d, J = 10.51 Hz, 1 H) 4.55 (dt, J = 10.29,5.07 Hz, 1 H) 3.86-3.99 (m, 1 H) 3.61 (td, J = 11.35, 7.43 Hz, 1 H) 2.22(s, 3 H) 2.00- 2.11(m, 1 H) 1.76-1.99 (m, 2H) 1.41- 1.54 (m, 1 H) 44

424.4 (400 MHz, MeOD) δppm 7.95 (br t, J = 7.87 Hz, 1 H) 7.32-7.43 (m, 3H) 7.04- 7.15 (m, 3 H) 6.91-6.99 (m, 1 H) 6.80- 6.88 (m, 1 H)5.76-5.92(m, 1 H) 5.17 (d, J = 9.88 Hz, 1 H) 4.50-4.59 (m, 1 H) 3.84-3.94 (m, 1 H) 3.57-3.68 (m, 1 H) 2.02- 2.11 (m, 1 H) 1.80-1.99 (m, 2H)1.47- 1.59 (m, 1 H) 45

442.4 (500 MHz, CHLOROFORM-d) δ ppm 7.38 (s, 1 H) 7.09 (td, J = 7.98,5.91 Hz, 1 H) 6.97 (d, J = 6.52 Hz, 2H) 6.80-6.88 (m, 2 H) 6.68 (d, J =10.11 Hz, 1 H) 6.63 (d, J = 7.66 Hz, 1 H) 5.33 (dd, J = 9.52, 3.61 Hz, 1H) 4.41-4.47 (m, 1 H) 4.28 (d, J = 9.46 Hz, 1 H) 3.94-4.01 (m, 1 H) 3.66(td, J = 11.41, 7.21 Hz, 1 H) 2.09-2.29 (m, 1 H) 1.86-2.09 (m, 2H) 1.58(qd, J = 11.88, 6.80 Hz, 1 H) 46

424.3 (500 MHz, CD3OD) δ ppm 7.47-7.35 (m, 1H), 7.29 (s, 1H), 7.17-7.05(m, 7H), 6.00 (d, J = 9.7 Hz, 1H), 4.69 (d, J = 10.0 Hz, 1H), 4.56 (s,1H), 3.99-3.87 (m, 1H), 3.69-3.56 (m, 1H), 2.06 (s, 2H), 1.89 (s, 1H),1.60-1.43 (m, 1H) 47

423.4 (500 MHz, CD3OD) δ ppm 7.43 (d, J = 7.3 Hz, 2H), 7.41-7.33 (m,2H), 7.07-7.01 (m, 1H), 6.99 (dd, J = 8.6, 5.3 Hz, 2H), 6.81 (s, 2H),5.75 (dd, J = 9.6, 3.6 Hz, 1H), 4.59 (d, J = 9.6 Hz, 1H), 4.51 (dt, J =9.8, 4.7 Hz, 1H), 3.93-3.82 (m, 1H), 3.75- 3.59 (m, 1H), 2.06 (dt, J =12.8, 6.7 Hz, 1H), 1.96-1.89 (m, 1H), 1.89-1.77 (m, 1H), 1.67-1.55 (m,1H) 48

442.2 (500 MHz, CD3OD) δ ppm 7.47-7.40 (m, 1H), 7.38 (s, 1H), 7.14 (d, J= 8.1 Hz, 2H), 7.11 (d, J = 9.0 Hz, 2H), 6.88 (t, J = 8.2 Hz, 2H), 5.99(d, J = 10.6 Hz, 1H), 4.72 (d, J = 10.0 Hz, 1H), 4.56 (s, 1H), 3.99-3.86(m, 1H), 3.63 (d, J = 7.1 Hz, 1H), 2.05 (s, 2H), 1.88 (s, 1H), 1.51 (d,J = 7.5 Hz, 1H) 49

442.4 (500 MHz, CD3OD) δ ppm 7.49-7.41 (m, 1H), 7.37 (s, 1H), 7.13 (t, J= 9.5 Hz, 3H), 6.95 (d, J = 10.6 Hz, 1H), 6.89 (t, J = 9.9 Hz, 2H), 6.00(d, J = 10.7 Hz, 1H), 4.74 (d, J = 10.1 Hz, 1H), 4.57 (s, 1H), 3.97-3.88(m, 1H), 3.63 (d, J = 8.1 Hz, 1H), 2.05 (dd, J = 18.0, 11.8 Hz, 2H),1.89 (s, 1H), 1.55- 1.44 (m, 1H) 50

460.4 (500 MHz, CD3OD) δ ppm 7.51 (s, 1H), 7.47 (q, J = 7.1, 6.6 Hz,1H), 7.44-7.36 (m, 2H), 7.09 (t, J = 8.0 Hz, 1H), 6.86- 6.79 (m, 2H),5.77 (d, J = 9.8 Hz, 1H), 4.64 (d, J = 10.2 Hz, 1H), 4.51 (s, 1H), 3.92-3.81 (m, 1H), 3.71-3.61 (m, 1H), 2.02 (d, J = 10.7 Hz, 1H), 1.95-1.87(m, 1H), 1.85 (d, J = 9.7 Hz, 1H), 1.50 (dd, J = 11.6, 6.9 Hz, 1H)

Example 51.(9aR,10S)-10-((S)-(2-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Step 1: Tert-butyl (R)-2-((1S,2S)-2-(2-fluorophenyl)-1-((methylsulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl(R)-2-((1S,2S)-2-(2-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate(300 mg, 0.778 mmol) in pyridine (9 mL) at 0° C. was addedmethanesulfonyl chloride (0.910 mL, 11.67 mmol). After 5 min, the icebath was removed and the reaction was stirred for 2 h at RT. Thereaction mixture was partitioned between DCM and water. The DCM layerwas separated and washed sequentially with 1N aqueous HCl, saturatedaqeuous NaHCO₃ and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. Silica gel column chromatography(EtOAc/heptane) provided tert-butyl(R)-2-((1S,2S)-2-(2-fluorophenyl)-1-((methylsulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxylate(325 mg, white foam) in 90% yield. MS m/z 408.3 (MH⁺-tBu).

Step 2:(1R,7aR)-1-((S)-(2-fluorophenyl)(phenyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one

A solution of tert-butyl(R)-2-((1S,2S)-2-(2-fluorophenyl)-1-((methylsulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxylate(325 mg, 0.701 mmol) in pyridine (4 mL) was heated at 120° C. for 2 h ina microwave reactor. Silica gel column chromatography (EtOAc/heptane)provided(1R,7aR)-1-((S)-(2-fluorophenyl)(phenyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one(150 mg) in 69% yield. MS m/z 312.4 (MH⁺).

Step 3:(1R,2S)-2-(2-fluorophenyl)-2-phenyl-1-((R)-pyrrolidin-2-yl)ethan-1-olHydrochloride

Added 6N aqueous HCl solution to a solution of(1R,7aR)-1-((S)-(2-fluorophenyl)(phenyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one (150 mg, 0.482 mmol)in dioxane (2 mL) and the mixture was heated at 90° C. for 2 days in asealed vial until the reaction was complete. The reaction was thenconcentrated to afford crude(1R,2S)-2-(2-fluorophenyl)-2-phenyl-1-((R)-pyrrolidin-2-yl)ethan-1-olhydrochloride, which was used in the next step without furtherpurification. MS m/z 286.4 (MH⁺).

Step4:1-benzyl-5-(benzyloxy)-3-((R)-2-((1R,2S)-2-(2-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carbonyl)pyridazin-4(1H)-one

Added Huenig's Base (0.331 mL, 1.892 mmol) and HATU (234 mg, 0.615 mmol)to a solution of1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid(175 mg, 0.520 mmol) in DCM (2 mL) at RT. Stirred at RT for 15 min, thenadded a solution of crude(1R,2S)-2-(2-fluorophenyl)-2-phenyl-1-((R)-pyrrolidin-2-yl)ethan-1-olhydrochloride (135 mg, 0.473 mmol) in DCM (2 mL) and Huenig's Base(0.331 mL, 1.892 mmol). The mixture was stirred at RT for 30 min. Themixture was then diluted with DCM and washed with water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Silicagel column chromatography (EtOAc/EtOH/heptane) provided1-benzyl-5-(benzyloxy)-3-((R)-2-((1R,2S)-2-(2-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carbonyl)pyridazin-4(1H)-one(270 mg, foamy solid) in 95% yield. MS m/z 604.7 (MH⁺).

Step 5:(1R,2S)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(2-fluorophenyl)-2-phenylethylMethanesulfonate

To a solution of1-benzyl-5-(benzyloxy)-3-((R)-2-((1R,2S)-2-(2-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carbonyl)pyridazin-4(1H)-one(270 mg, 0.447 mmol) in 2,6-lutidine (6 mL, 51.5 mmol) was addedmethanesulfonyl chloride (0.697 mL, 8.95 mmol) in an ice bath. After 5min, the bath was removed and reaction mixture was stirred for 3 h atRT. LC-MS shows major, [M+H]+ 682.5/1.07 min corresponds to desiredproduct. The reaction mixture was then partitioned between DCM andwater. The DCM layer was separated and washed sequentially with 1Naqueous HCl, saturated aqueous NaHCO₃ and brine. The DCM layer was thendried over Na₂SO₄, filtered and concentrated. Silica gel columnchromatography (EtOAc/heptane) provided(1R,2S)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(2-fluorophenyl)-2-phenylethylmethanesulfonate (245 mg, brown solid) in 80% yield. MS m/z 682.6 (MH⁺).

Step 6:(1R,2S)-2-(2-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-phenylethylMethanesulfonate

To a solution of(1R,2S)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(2-fluorophenyl)-2-phenylethylmethanesulfonate (245 mg, 0.359 mmol) in methanol (6 mL) was added HCl(4.0 M in dioxane, 0.180 mL, 0.719 mmol) then the solution was purgedwith nitrogen. Added 10% palladium on carbon (115 mg, 0.108 mmol) andattached a hydrogen balloon. The flask was evacuated and refilled withhydrogen (3 times) and then stirred vigorously for 2 h at RT under aballoon of hydrogen. Added more palladium on carbon (115 mg, 0.108 mmol)and stirred for another 2 h at RT. The reaction mixture was filteredthrough celite, and the filter cake was washed with MeOH. The filtratewas concentrated to give crude(1R,2S)-2-(2-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-phenylethylmethanesulfonate, which was used in the next step without furtherpurification. MS m/z 502.3 (MH⁺).

Step 7:(9aR,10S)-10-((S)-(2-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

To a solution of crude(1R,2S)-2-(2-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-phenylethylmethanesulfonate (180 mg, 0.341 mmol) in DMF (5 mL) was added potassiumcarbonate (188 mg, 1.364 mmol) and the mixture was stirred overnight atRT. The reaction was filtered through a 1 micron filter and purified byreverse phase HPLC. Product fractions were combined, frozen andlyophilized to afford a formate salt of(9aR,10S)-10-((S)-(2-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione(69 mg, 0.151 mmol, white solid) in 44% yield over two steps. ¹H NMR(400 MHz, CD₃OD) δ ppm 7.55 (d, J=7.63 Hz, 2H) 7.42 (t, J=7.65 Hz, 2H)7.37 (s, 1H) 7.27-7.34 (m, 1H) 7.03-7.13 (m, 2H) 6.88-6.95 (m, 1H) 6.83(dd, J=10.37, 8.31 Hz, 1H) 5.82 (dd, J=9.88, 3.57 Hz, 1H) 4.92 (br d,J=9.98 Hz, 1H) 4.49-4.62 (m, 1H) 3.82-4.00 (m, 1H) 3.57-3.73 (m, 1H)1.98-2.10 (m, 1H) 1.77-1.94 (m, 2H) 1.56-1.70 (m, 1H). MS m/z 406.4(MH⁺).

TABLE 1e Additional compounds prepared by the method of Example 51.Example Mass No. Structure M + H 1H NMR 52

424.4 (400 MHz, MeOD) δ ppm 7.51-7.62 (m, 1 H) 7.25-7.47 (m, 3 H)7.00-7.12 (m, 3 H) 6.90-6.96 (m, 2 H) 5.67-5.76 (m, 1 H) 4.56 (d, J =9.24 Hz, 1 H) 4.46-4.53 (m, 1 H) 3.82-3.92 (m, 1 H) 3.67 (td, J = 11.05,7.48 Hz, 1 H) 2.04-2.15 (m, 1 H) 1.92-2.02 (m, 1 H) 1.80-1.91 (m, 1 H)1.57-1.73 (m, 1 H) 53

442.3 (400 MHz, MeOD) δppm 7.52-7.64 (m, 1 H) 7.37 (s, 2 H) 7.26-7.35(m, 1 H) 7.08-7.17 (m, 1 H) 6.98-7.06 (m, 1 H) 6.90-6.97 (m,1 H)6.81-6.89 (m, 1 H) 5.81 (dd, J = 9.63, 3.57 Hz, 1 H) 4.91 (br s, 1 H)4.52 (dt, J = 10.40, 5.04 Hz, 1 H) 3.83-3.94 (m, 1 H) 3.64 (td, J =11.24, 7.26 Hz, 1 H) 2.03-2.14 (m, 1 H) 1.77-2.02 (m, 2 H) 1.60 (qd, J =11.71, 6.68 Hz, 1 H) 54

442.4 (400 MHz, MeOD) δppm 7.39 (s, 1 H) 7.26 (br d, J = 6.70 Hz, 2 H)7.11-7.19 (m, 1 H) 7.00-7.07 (m, 1 H) 6.82-6.98 (m, 3 H) 5.84(dd, J =9.56, 3.55 Hz, 1 H) 4.94 (br d, J = 9.73 Hz, 1 H) 4.48-4.59 (m, 1 H)3.83-3.93 (m, 1 H) 3.65 (td, J = 11.22, 7.29 Hz, 1 H) 1.97-2.13 (m, 2H)1.80-1.92 (m, 1 H) 1.61 (qd, J = 11.79, 6.77 Hz, 1 H) 55

424.4 (400 MHz, MeOD) δppm 7.29-7.51 (m, 4 H) 7.00-7.18 (m, 3 H)6.90-6.98 (m, 1 H) 6.80-6.89 (m, 1 H) 5.83 (dd, J = 9.73, 3.57 Hz, 1H)4.94 (br d, J = 9.78 Hz, 1 H) 4.53 (dt, J = 10.37, 4.99 Hz, 1 H)3.82-3.93 (m, 1 H) 3.65 (td, J = 11.30, 7.48 Hz, 1 H) 2.02-2.11 (m, 1 H)1.78-2.00 (m, 2 H) 1.61 (qd, J = 11.65, 6.77 Hz, 1 H) 56

438.4 (400 MHz, MeOD) δppm 7.93 (dd, J = 8.61, 5.58 Hz, 1 H) 7.33 (s, 1H) 6.91- 7.20 (m, 5 H) 6.79-6.88 (m, 1 H) 5.84 (dd, J = 9.93, 3.42 Hz, 1H) 4.97 (br d, J = 9.98 Hz, 1 H) 4.47-4.60 (m, 1 H) 3.87-4.01 (m, 1 H)3.54-3.67 (m, 1 H) 2.15 (s, 3 H) 2.01-2.09 (m, 1 H) 1.79- 1.95 (m, 2 H)1.30-1.43 (m, 1 H) 57

424.2 (400 MHz, DMSO) δ ppm 7.62 (dd, J = 8.39, 5.50 Hz, 2 H) 7.14-7.24(m, 3 H) 7.06-7.14 (m, 1 H) 6.98-7.05 (m, 1 H) 6.82-6.96 (m, 2H) 5.78(dd, J = 10.15, 3.45 Hz, 1 H) 4.82 (d, J = 10.17 Hz, 1 H) 4.48 (dt, J =9.99, 4.96 Hz, 1 H) 3.67-3.76 (m, 1 H) 3.55 (td, J = 10.92, 7.31 Hz, 1H)1.83-1.94 (m, 1 H) 1.72- 1.80 (m, 1 H) 1.59-1.71 (m, 1 H) 1.33 (qd, J= 11.59, 6.80 Hz, 1 H) 58

406.4 (400 MHz, d-DMSO) δ ppm 7.59 (d, J = 7.53 Hz, 2 H) 7.36 (t, J =7.18 Hz, 2 H) 7.19-7.28 (m, 2 H) 6.94-7.03 (m, 2 H) 6.88 (t, J = 8.83Hz, 2 H) 5.67 (dd, J = 9.76, 3.55 Hz, 1 H) 4.59 (d, J = 9.78 Hz, 1 H)4.39-4.53 (m, 1 H) 3.65-3.89 (m, 1 H) 3.44-3.64 (m, 1 H) 1.80-1.96 (m, 1H) 1.59-1.80 (m, 2 H) 1.30-1.46 (m, 1 H) 59

406.4 (500 MHz, CHLOROFORM-d) δ ppm 7.34-7.49 (m, 5 H) 7.29 (s, 2 H)7.02- 7.08 (m, 1 H) 6.80 (br t, J = 8.28 Hz, 1 H) 6.73 (br d, J = 9.81Hz, 1 H) 6.65 (br d, J = 7.68 Hz, 1 H) 5.42-5.46 (m, 1 H) 4.39-4.45 (m,1 H) 4.31 (br d, J = 9.81 Hz, 1 H) 3.91-3.97 (m, 1 H) 3.60-3.68 (m, 1 H)2.01-2.11 (m, 1 H) 1.79-1.92 (m, 2H) 1.51-1.62 (m, 1 H) 60

424.3 (400 MHz, d-DMSO) δ ppm 7.81 (m, 1 H) 7.3-7.15 (m, 3 H) 7.1 (m, 1H) 6.9 (m, 1 H) 6.9-6.8 (m, 2H) 5.75 (dd, J = 8, 4 Hz, 1 H) 4.75 (d, J =8 Hz) 4.5 (m, 1H) 3.75 (m, 1H) 3.6 (m, 1H) 1.95 (m, 1H) 1.8 (m, 1H) 1.7(m, 1H) 1.35 (m, 1H) 61

424.3 (500 MHz, CD3OD) δ ppm 7.51 (d, J = 7.5 Hz, 2H), 7.41 (s, 1H),7.38 (t, J = 7.2 Hz, 2H), 7.29 (t, J = 7.1 Hz, 1H), 7.22-7.10 (m, 1H),6.76 (t, J = 9.0 Hz, 2H), 6.07 (d, J = 10.6 Hz, 1H), 4.98 (d, J = 11.0Hz, 1H), 4.59 (s, 1H), 3.93- 3.82 (m, 1H), 3.64-3.53 (m, 1H), 1.97 (d, J= 6.2 Hz, 2H), 1.82 (s, 1H), 1.51- 1.40 (m, 1H) 62

442.4 (500 MHz, CD3OD) δ ppm 7.45-7.32 (m, 3H), 7.30 (d, J = 7.1 Hz,1H), 7.21 (s, 1H), 7.05 (t, J = 7.9 Hz, 1H), 6.79 (s, 2H), 6.06 (s, 1H),5.00 (d, J = 9.8 Hz, 1H), 4.59 (s, 1H), 3.88 (s, 1H), 3.59 (s, 1H), 2.01(s, 2H), 1.84 (s, 1H), 1.46 (s, 1H) 63

442.4 (500 MHz, CD3OD) δ ppm 7.53 (s, 2H), 7.39 (s, 1H), 7.10 (s, 3H),6.76 (s, 2H), 6.02 (s, 1H), 4.98 (d, J = 11.6 Hz, 1H), 4.57 (s, 1H),3.87 (s, 1H), 3.58 (s, 1H), 1.97 (s, 2H), 1.81 (s, 1H), 1.45 (s, 1H) 64

460.9 (500 MHz, CD3OD) δ ppm 7.47 (t, J = 7.2 Hz, 2H), 7.42 (s, 1H),7.11 (d, J = 7.5 Hz, 1H), 6.85 (s, 1H), 6.74 (d, J = 8.5 Hz, 2H), 5.73(d, J = 9.5 Hz, 1H), 4.64 (d, J = 9.7 Hz, 1H), 4.51 (s, 1H), 3.93-3.83(m, 1H), 3.72-3.61 (m, 1H), 2.09 (s, 1H), 1.99 (s, 1H), 1.88 (s, 1H),1.65-1.53 (m, 1H)

General Synthesis of Chiral N-CBZ Amino Alcohols

Step G-1: Tert-butyl(R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylate

Added a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 26.3mL, 26.3 mmol) dropwise to a solution of diethyl2,3-difluorobenzylphosphonate (7.13 g, 25.1 mmol) in THF (84 mL) at 0°C. Stirred at 0° C. for 1 h, then added (R)-tert-butyl2-formylpyrrolidine-1-carboxylate (5.0 g, 25.1 mmol) dropwise. Reactionmixture was stirred in ice bath for 1 h and then slowly warmed to RTover 1 h and then stirred for an additional 2 h at RT. The reaction wasquenched with water and extracted with EtOAc (twice). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/heptane) providedtert-butyl (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylate (6.87g, white solid) in 88% yield. MS m/z 254.3 (M-tBu+H).

Step G-2: (R,E)-2-(2,3-difluorostyryl)pyrrolidine Hydrochloride

Added a solution of HCl (4.0 M in dioxane, 19.6 ml, 78 mmol) totert-butyl (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylate (6.07g, 19.6 mmol) at RT and stirred for 1 h. The reaction mixture was thenconcentrated to give crude (R,E)-2-(2,3-difluorostyryl)pyrrolidinehydrochloride, which was used in the next step without furtherpurification. MS m/z 210.2 (MH⁺).

Step G-3: Benzyl (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylate

Benzylchloroformate (3.1 ml, 21.6 mmol) was added dropwise to a solutionof triethylamine (6.84 ml, 49.1 mmol) and(R,E)-2-(2,3-difluorostyryl)pyrrolidine hydrochloride (4.11 g, 19.6mmol) in DCM (98 ml) at 0° C. and the mixture was allowed to warm to RTand stirred overnight. The reaction was then diluted with additionalDCM, washed successively with water then brine, dried with Na₂SO₄,filtered and concentrated. Silica gel column chromatography(EtOAc/heptane) provided benzyl(R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylate (6.67 g, colorlessoil) in 99% yield over two steps. MS m/z 344.3 (MH⁺).

Step G-4: Benzyl(R)-2-((2S,3S)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylateand benzyl(R)-2-((2R,3R)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate

To (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylate (5.9 g, 17.2mmol) in DCM (286 mL) was added mCPBA (21.2 g, 86 mmol). The reactionmixture was stirred at RT overnight. The reaction was quenched withwater and extracted with DCM (twice). The combined organic extracts werewashed sequentially with saturated aqueous Na₂S₂O₃, saturated aqueousNaHCO₃ and brine. The organic layer was then dried over Na₂SO₄, filteredand concentrated. Silica gel column chromatography (EtOAc/heptane)provided an inseparable mixture of benzyl(R)-2-((2S,3S)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylateand benzyl(R)-2-((2R,3R)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate(5.16 g, colorless oil) in 84% yield. The mixture was used in the nextstep without further purification.

Step G-5: Benzyl(R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylateand benzyl(R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate

Added copper(I) bromide-dimethyl sulfide complex (286 mg, 1.39 mmol) toa mixture of benzyl(R)-2-((2S,3S)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylateand benzyl(R)-2-((2R,3R)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate(500 mg, 1.39 mmol) in THF (8 mL) at RT. Cooled to between −20 and −30°C. in an acetone bath with periodic dry ice additions. A solution of(4-fluorophenyl)magnesium bromide (1.0 M in THF, 8.35 mL, 8.35 mmol) wasadded dropwise. Stirred 10 min and allowed the temperature to warm to 0°C. Added 2 equiv more of (4-fluorophenyl)magnesium bromide and stirredanother 30 min. The reaction was quenched with saturated aqueous NH₄Clsolution and extracted with EtOAc (2 times). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated. Silica gelcolumn chromatography (EtOAc/heptane) provided benzyl(R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate(88 mg, colorless oil, eluted first) in 14% yield and benzyl(R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (350 mg, eluted second) in 55% yield. MS m/z456.4 (MH+).

Example 65.(9aR,10S)-10-((R)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Step 1: Benzyl(R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate

To a solution of benzyl(R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate(88 mg, 0.19 mmol) in pyridine (2.5 mL) at 0° C. was addedmethanesulfonyl chloride (0.23 mL, 2.9 mmol). After 5 min, the ice bathwas removed and the reaction was stirred for 2 h at RT. The reactionmixture was partitioned between DCM and water. The DCM layer wasseparated and washed sequentially with 1N aqueous HCl, saturated aqueousNaHCO₃ and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/heptane) providedbenzyl(R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate(85 mg) in 82% yield. MS m/z 534.5 (MH⁺).

Step 2:(1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((R)-pyrrolidin-2-yl)ethylMethanesulfonate Hydrochloride

A solution of benzyl(R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate(85 mg, 0.16 mmol) in methanol (4 mL) and HCl (4.0 M in dioxane, 0.080mL, 0.32 mmol) was purged with nitrogen. Added 10% palladium on carbon(68 mg, 0.064 mmol) and attached a hydrogen balloon. The flask wasevacuated and refilled with hydrogen (3 times) and then stirredvigorously at RT under a balloon of hydrogen. After 2H, the reactionmixture was filtered through celite, and the filter cake was washed withMeOH. The filtrate was concentrated to give crude(1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((R)-pyrrolidin-2-yl)ethylmethanesulfonate hydrochloride, which was used in the next step withoutfurther purification. MS m/z 400.4 (MH+).

Example 65.(9aR,10S)-10-((R)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Prepared from(1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((R)-pyrrolidin-2-yl)ethylmethanesulfonate hydrochloride by the method of Example 32, steps 3-5.¹H NMR (400 MHz, CD₃OD) δ ppm 7.79-7.65 (m, 1H), 7.42 (s, 1H), 7.37-7.21(m, 2H), 7.02 (dd, J=8.6, 5.3 Hz, 2H), 6.85 (t, J=8.7 Hz, 2H), 5.79 (dd,J=9.6, 3.7 Hz, 1H), 4.74 (d, J=9.6 Hz, 1H), 4.62 (s, 1H), 4.53 (dt,J=10.2, 4.8 Hz, 1H), 3.90 (dd, J=12.7, 8.8 Hz, 1H), 3.65 (td, J=11.1,7.0 Hz, 1H), 2.04 (ddt, J=38.5, 18.2, 6.4 Hz, 2H), 1.94 (s, 1H), 1.51(qd, J=11.7, 6.7 Hz, 1H). MS m/z 442.4 (MH+).

TABLE 1f Additional compounds prepared by the method Example 65. ExampleMass No. Structure M + H 1H NMR 66

420.3 (400 MHz, MeOD) δ ppm 7.84 (br dd, J = 13.01, 7.97 Hz, 1 H) 7.35(br t, J = 12.79 Hz, 2 H) 7.07-7.26 (m, 2 H) 6.94 (br s, 2 H) 6.67-6.84(m, 2 H) 5.79 (br t, J = 10.00 Hz, 1 H) 4.48 (br d, J = 10.07 Hz, 2 H)3.90 (br d, J = 8.41 Hz, 1 H) 3.60 (br s, 1 H) 2.14 (br d, J = 13.60 Hz,3 H)1.73-2.04 (m, 3 H) 1.36-1.38 (m, 1 H) 1.31 (br s, 1 H) 67

420.3 (400 MHz, MeOD) δ ppm 7.60 (br d, J = 16.24 Hz, 1 H) 7.05-7.35 (m,6 H) 6.97 (dt, J = 16.93, 8.53 Hz, 2 H) 5.28- 5.45 (m, 2 H) 4.30 (brs, 1H) 3.53- 3.73 (m, 2 H) 2.26 (br d, J = 16.77 Hz, 3 H) 1.91 (br d, J =16.82 Hz, 1 H) 1.73 (br s, 1 H) 1.39 (ddd, J = 17.15, 11.11, 5.97 Hz, 2H) 68

406.2 (400 MHz, MeOD) δ ppm 7.59 (dd, J = 8.63, 5.26 Hz, 2 H) 7.36 (s, 1H) 7.14 (t, J = 8.71 Hz, 2 H) 7.02-7.09 (m, 3 H) 6.93 (dd, J = 6.55,2.84 Hz, 2 H) 5.72 (dd, J = 9.39, 3.62 Hz, 1 H) 4.42- 4.60 (m, 2 H)3.80-3.93 (m, 1 H) 3.68 (td, J = 10.99, 7.46 Hz, 1 H) 2.02-2.11 (m, 1 H)1.77-1.96 (m, 2 H) 1.57-1.72 (m, 1 H) 69

424.3 (400 MHz, MeOD) δ ppm 1.54-1.68 (m, 1 H) 1.77-1.96 (m, 2 H) 2.00-2.10 (m, 1 H) 3.59-3.76 (m, 1 H) 3.80- 3.95 (m, 1 H) 4.44-4.65 (m, 2 H)5.72 (dd, J = 9.59, 3.62 Hz, 1 H) 6.80 (t, J = 8.71 Hz, 2 H) 6.97 (dd, J= 8.61, 5.33 Hz, 2 H) 7.15 (t, J = 8.71 Hz, 2 H) 7.42 (s, 1 H) 7.58(dd,J = 8.63, 5.26 Hz, 2 H) 70

442.2 (400 MHz, MeOD) δ ppm 7.59 (dd, J = 8.63, 5.21 Hz, 2 H) 7.45 (s, 1H) 7.16 (t, J = 8.68 Hz, 2 H) 6.88-7.03 (m, 2 H) 6.71-6.80 (m, 1 H)5.73(dd, J = 9.81, 3.55 Hz, 1 H) 4.59 (d, J = 9.83 Hz, 1 H) 4.49 (br dd, J =10.25, 5.01 Hz, 1 H) 3.81-3.95 (m, 1 H) 3.58-3.73 (m, 1 H) 1.98-2.10(m,1 H) 1.73-1.94 (m, 2 H) 1.46-1.65 (m, 1 H) 71

438.2 (400 MHz, MeOD) δ ppm 7.54 (br s, 2 H) 7.43 (s, 1 H) 7.00-7.29 (m,3 H) 6.54-6.83 (m, 2 H) 5.86 (br s, 1 H) 4.82 (br s, 1 H) 4.44-4.65 (m,1 H) 3.76-3.99 (m, 1 H) 3.65 (td, J = 11.29, 7.36 Hz, 1 H) 2.23 (br s, 3H) 1.99- 2.09 (m, 1 H) 1.71-1.99 (m, 2 H) 1.45- 1.67 (m, 1 H) 72

460.4 (400 MHz, MeOD) δ ppm 7.76 (br t, J = 6.92 Hz, 1 H) 7.46 (s, 1 H)7.21- 7.41 (m, 2 H) 7.04-7.18 (m, 1 H) 6.65- 6.87 (m, 2 H) 5.86 (dd, J =9.81,3.55 Hz, 1 H) 5.11 (d, J = 9.88 Hz, 1 H) 4.54 (dt, J = 10.39, 4.98Hz, 1 H) 3.84-3.97 (m, 1 H) 3.61 (td, J = 11.29, 7.26 Hz, 1 H) 2.04-2.13(m, 1 H) 1.96-2.03(m, 1 H) 1.80-1.92 (m, 1 H) 1.48 (qd, J = 11.83, 6.72Hz, 1 H) 73

424.4 1H NMR (400 MHz, MeOD) δ ppm δ ppm 1.61-1.88 (m, 3 H) 1.98-2.10(m, 1 H) 3.55-3.80 (m, 2 H) 4.10 (td, J = 10.59, 5.72 Hz, 1H) 5.17 (d, J= 5.53 Hz, 1 H) 5.34 (dd, J = 10.78, 5.60 Hz, 1 H) 7.04 (td, J = 8.64,6.43 Hz, 4 H) 7.23- 7.43 (m, 4 H) 7.67 (s, 1 H) 74

442.4 (400 MHz, MeOD) δppm 7.74 (br t, J = 6.99 Hz, 1 H) 7.40 (s, 1 H)7.37 (br s, 1 H) 7.23-7.36 (m, 1 H) 7.06-7.16 (m, 1 H) 6.82-6.91 (m, 1H) 6.72-6.81 (m, 2 H) 5.81 (dd, J = 9.61, 3.59 Hz, 1 H) 4.76 (d, J =9.63 Hz, 1 H) 4.61 (br s, 1 H) 4.48-4.55 (m, 1 H) 3.84-3.94 (m, 1 H)3.65(td, J = 11.25, 7.38 Hz, 1 H) 2.04-2.14 (m, 1 H) 1.95-2.03 (m, 1 H)1.80-1.92 (m, 1 H) 1.50 (qd, J = 11.67, 6.80 Hz, 1 H) 75

442.3 (400 MHz, DMSO-d6) δ 7.67 (dd, J = 8.6, 5.5 Hz, 2H), 7.32 (s, 1H),7.21 (t, J = 8.8 Hz, 2H), 6.95 (tt, J = 9.2, 2.4 Hz, 1H), 6.72 (dd, J =8.8, 2.5 Hz, 2H), 5.72 (d, J = 3.6 Hz, 1H), 4.75 (d, J = 10.1 Hz, 1H),4.53-4.39 (m, 1H), 3.79- 3.64 (m, 1H), 3.61-3.49 (m, 1H), 1.86 (dd, J =12.8, 6.8 Hz, 1H), 1.77- 1.57 (m, 2H), 1.27 (qd, J = 11.3, 6.7 Hz, 1H)76

460.3 (400 MHz, DMSO-d6) δ 7.88-7.77 (m, 1H), 7.53-7.39 (m, 2H), 7.31(s, 1H), 6.97 (tt, J = 9.3, 2.4 Hz, 1H), 6.73 (dd, J = 8.7, 2.4 Hz, 2H),5.73 (dd, J = 10.2, 3.6 Hz, 1H), 4.77 (d, J = 10.2 Hz, 1H), 4.46 (dt, J= 10.3, 5.2 Hz, 1H), 3.76-3.65 (m, 1H), 3.53 (td, J = 11.1, 7.0 Hz, 1H),1.88 (dt, J = 12.9, 6.6 Hz, 1H), 1.78 (dt, J = 12.2, 6.1 Hz, 1H),1.72-1.58 (m, 1H), 1.24 (qd, J = 11.5, 6.6 Hz, 1H) 77

442.5 (400 MHz, DMSO-d6) δ 7.87-7.72 (m, 1H), 7.53-7.36 (m, 2H), 7.24(s, 1H), 7.16-7.04 (m, 1H), 6.89 (td, J = 8.6, 2.5 Hz, 1H), 6.85-6.72(m, 2H), 5.71 (dd, J = 10.0, 3.6 Hz, 1H), 4.71 (d, J = 10.0 Hz, 1H),4.46 (dd, J = 10.7, 5.2 Hz, 1H), 3.75-3.64 (m, 1H), 3.62- 3.50 (m, 1H),1.89 (dd, J = 12.6, 6.4 Hz, 1H), 1.79 (dt, J = 12.3, 5.9 Hz, 1H),1.73-1.59 (m, 1H), 1.31 (qd, J = 11.5, 6.6 Hz, 1H). 78

460.5 (400 MHz, DMSO-d6) δ 7.86-7.72 (m, 1H), 7.44 (dd, J = 9.6, 6.8 Hz,2H), 7.30 (d, J = 4.0 Hz, 1H), 7.16 (q, J = 9.1 Hz, 1H), 7.11-7.03 (m,1H), 6.80 (d, J = 10.0 Hz, 1H), 5.71 (dd, J = 10.1, 3.7 Hz, 1H), 4.73(d, J = 10.0 Hz, 1H), 4.45 (s, 1H), 3.70 (t, J = 10.3 Hz, 1H), 3.54 (td,J = 10.5, 6.8 Hz, 1H), 1.88 (s, 1H), 1.77 (dt, J = 12.3, 6.0 Hz, 1H),1.71-1.59 (m, 1H), 1.33-1.18 (m, 1H). 79

460.4 (400 MHz, DMSO-d6) δ 8.09 (q, J = 8.3 Hz, 1H), 7.33-7.13 (m, 3H),7.10- 6.96 (m, 2H), 6.87 (td, J = 8.5, 2.5 Hz, 1H), 5.85 (dd, J = 10.5,3.5 Hz, 1H), 4.86 (d, J = 10.2 Hz, 1H), 4.55- 4.43 (m, 1H), 3.77-3.65(m, 1H), 3.56- 3.42 (m, 2H), 1.96-1.79 (m, 2H), 1.70 (s, 1H), 1.31-1.11(m, 1H) 80

424.4 (400 MHz, CDCl3) δ ppm 7.29-7.42 (m, 2 H) 6.90-7.13 (m, 8 H) 5.34(dd, J = 9.17, 3.55 Hz, 1 H) 4.57 (d, J = 9.15 Hz, 1 H) 4.32-4.50 (m, 1H) 3.81- 4.02 (m, 1 H) 3.57-3.81 (m, 1 H) 2.08- 2.22 (m, 1 H) 1.82-2.07(m, 3 H) 1.59 (qd, J = 11.72, 6.85 Hz, 1 H) 81

442.4 (400 MHz, CDCl3) δ ppm 7.30-7.41 (m, 2 H) 6.88-7.14 (m, 4 H) 6.80-6.91 (m, 2 H) 5.34 (dd, J = 9.49, 3.52 Hz, 1 H) 4.55 (d, J = 9.54 Hz, 1H) 4.23- 4.49 (m, 1 H) 3.79-4.03 (m, 1 H) 3.54-3.79 (m, 1 H) 2.07-2.18(m, 1 H) 1.81-2.07 (m, 1 H) 1.53 (qd, J = 11.76, 6.77 Hz, 1 H) 82

460.4 (400 MHz, CDCl3) δ ppm 7.43 (s, 1 H) 7.29-7.42 (m, 1 H) 7.03-7.13(m, 2 H) 7.0-6.95 (m, 2H) 6.94 (m, 1H) 5.35 (dd, J = 9.81, 3.43 Hz, 1 H)4.53 (d, J = 10.17 Hz, 3 H) 4.42 (m, 1H) 3.95 (m, 1H) 3.63 (m, 1H2.13(m, 1H) 1.99 (s, 3 H) 1.88 (m, 1H) 1.48 (m, 1H) 83

424.4 (500 MHz, Methanol-d4) δ 7.60 (s, 1H), 7.58 (s, 1H), 7.51-7.42 (m,3H), 7.36 (t, J = 7.4 Hz, 1H), 6.73-6.60 (m, 3H), 5.79 (d, J = 9.8 Hz,1H), 4.61 (d, J = 9.9 Hz, 1H), 4.57-4.47 (m, 1H), 3.95- 3.83 (m, 1H),3.70 (t, J = 9.6 Hz, 1 H), 2.02 (d, J = 11.0 Hz, 1H), 1.95-1.77 (m, 2H),1.65-1.50 (m, 1H). 84

443.4 (500 MHz, Chloroform-d) δ 7.40-7.32 (m, 2H), 7.13-7.03 (m, 3H),6.83 (t, J = 8.3 Hz, 1H), 6.74 (d, J = 9.7 Hz, 1H), 6.67 (d, J = 7.7 Hz,1H), 5.35 (dd, J = 9.5, 3.6 Hz, 1H), 4.57 (d, J = 9.5 Hz, 1H), 4.46-4.37(m, 1H), 3.99-3.89 (m, 1H), 3.70-3.59 (m, 1H), 2.13 (dd, J = 13.2, 6.8Hz, 1H), 2.01 (dt, J = 12.4, 6.0 Hz, 1H), 1.96-1.85 (m, 1H), 1.60-1.47(m, 1H). 85

460.4 (500 MHz, Chloroform-d) δ 7.65-7.56 (m, 1H), 7.44 (s, 1H), 7.07(t, J = 7.8 Hz, 1H), 6.96-6.82 (m, 3H), 6.64 (d, J = 8.4 Hz, 1H), 5.41(dd, J = 9.8, 3.5 Hz, 1H), 4.54 (d, J = 9.7 Hz, 1H), 4.43 (dd, J = 10.5,5.5 Hz, 1H), 4.01-3.91 (m, 1H), 3.66 (td, J = 11.3, 7.1 Hz, 1H), 2.14(dt, J = 13.5, 6.9 Hz, 1H), 1.98 (dt, J = 12.2, 5.9 Hz, 1H), 1.91 (d, J= 13.2 Hz, 1H), 1.50 (qd, J = 11.6, 6.6 Hz, 1H). 86

420.4 (500 MHz, DMSO-d6) δ 7.63 (s, 2H), 7.21 (d, J = 1.5 Hz, 1H), 7.18(t, J = 8.5 Hz, 2H), 7.13 (s, 1H), 6.96 (s, 1H), 6.91 (s, 2H), 5.83 (s,1H), 4.78 (s, 1H), 4.52 (s, 1H), 3.74 (t, J = 10.4 Hz, 1H), 3.62 (q, J =10.7, 10.2 Hz, 2H), 2.21 (s, 3H), 1.91 (d, J = 8.0 Hz, 1H), 1.80 (s,1H), 1.71 (s, 1H), 1.38 (dd, J = 11.7, 6.8 Hz, 1H). 87

442.4 (500 MHz, Methanol-d4) δ 7.97 (q, J = 8.2 Hz, 1H), 7.44 (s, 1H),7.15 (t, J = 8.4 Hz, 1H), 7.02 (dd, J = 8.5, 4.5 Hz, 3H), 6.85 (t, J =8.5 Hz, 2H), 5.78 (dd, J = 9.5, 3.6 Hz, 1H), 4.70 (d, J = 9.4 Hz, 1H),4.53 (d, J = 8.5 Hz, 1H), 3.97- 3.87 (m, 1H), 3.65 (dd, J = 19.2, 10.7Hz, 1H), 2.10 (d, J = 8.0 Hz, 1H), 2.00 (dd, J = 12.3, 6.2 Hz, 1H), 1.90(s, 1H), 1.55 (dd, J = 11.7, 6.9 Hz, 1H). 88

424.4 (500 MHz, Methanol-d4) δ 7.98 (q, J = 8.0 Hz, 1H), 7.37 (d, J =1.3 Hz, 1H), 7.17-7.12 (m, 1H), 7.12-7.08 (m, 3H), 7.01 (t, J = 9.9 Hz,1H), 6.97 (d, J = 5.4 Hz, 2H), 5.86-5.74 (m, 1H), 4.68 (d, J = 9.3 Hz,1H), 4.60-4.50 (m, 1H), 3.99-3.87 (m, 1H), 3.73-3.61 (m, 1H), 2.11 (dd,J = 12.5, 6.4 Hz, 1H), 2.02 (dt, J = 12.6, 6.3 Hz, 1H), 1.92 (d, J =12.6 Hz, 1H), 1.69-1.55 (m, 1H). 89

442.3 (500 MHz, Methanol-d4) δ 7.98 (q, J = 8.3 Hz, 1H), 7.43 (d, J =1.5 Hz, 1H), 7.14 (dt, J = 21.3, 7.8 Hz, 2H), 7.04 (t, J = 9.8 Hz, 1H),6.87 (t, J = 8.6 Hz, 1H), 6.78 (d, J = 8.6 Hz, 2H), 5.81 (d, J = 7.4 Hz,1H), 4.72 (d, J = 9.6 Hz, 1H), 4.53 (d, J = 6.7 Hz, 1H), 3.97-3.88 (m,1H), 3.66 (q, J = 11.0, 10.4 Hz, 1H), 2.10 (s, 1H), 2.05-1.98 (m, 1H),1.90 (s, 1H), 1.55 (dd, J = 11.8, 6.8 Hz, 1H). 90

424.4 (400 MHz, DMSO-d6) δ 7.84 (t, J = 7.1 Hz, 1H), 7.37 (ddt, J =16.0, 13.4, 8.1 Hz, 2H), 7.21 (s, 1H), 7.14-7.03 (m, 3H), 6.98-6.85 (m,2H), 5.77 (dd, J = 9.6, 3.7 Hz, 1H), 4.64 (d, J = 9.6 Hz, 1H), 4.50 (dt,J = 10.0, 5.1 Hz, 1H), 3.73 (dd, J = 12.0, 8.4 Hz, 2H), 1.92 (ddt, J =30.6, 12.3, 6.1 Hz, 2H), 1.74 (q, J = 8.3, 6.0 Hz, 1H), 1.34 (qd, J =11.6, 6.6 Hz, 1H).

Example 91.(9aR,10S)-10-((S)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Step 1: Benzyl(R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate

To a solution of benzyl(R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate(350 mg, 0.77 mmol) in pyridine (2.5 mL) at 0° C. was addedmethanesulfonyl chloride (0.90 mL, 11.5 mmol). After 5 min, the ice bathwas removed and the reaction was stirred for 2 h at RT. The reactionmixture was partitioned between DCM and water. The DCM layer wasseparated and washed sequentially with 1N aqueous HCl, saturated aqueousNaHCO₃ and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/heptane) providedbenzyl(R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate(370 mg) in 90% yield. MS m/z 534.5 (MH⁺).

Step 2:(1R,7aR)-1-((S)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one

A solution of benzyl(R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate(370 mg, 0.693 mmol) in pyridine (2 mL) was heated at 150° C. for 3 h ina microwave reactor. Silica gel column chromatography (EtOAc/heptane)provided(1R,7aR)-1-((S)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one(200 mg) in 83% yield. MS m/z 348.4 (MH+).

Example 91.(9aR,10S)-10-((S)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Prepared from(1R,7aR)-1-((S)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-oneby the method of Example 51, steps 3-7. ¹H NMR (400 MHz, CD₃OD) δ ppm7.61 (dd, J=8.6, 5.2 Hz, 2H), 7.42 (s, 1H), 7.16 (t, J=8.7 Hz, 2H), 7.01(dtd, J=9.9, 7.9, 1.7 Hz, 1H), 6.96-6.80 (m, 2H), 5.85 (dd, J=10.0, 3.6Hz, 1H), 4.95-4.90 (m, 1H), 4.54 (dt, J=10.6, 4.9 Hz, 1H), 3.89 (dd,J=12.5, 8.7 Hz, 1H), 3.72-3.60 (m, 1H), 2.04 (qd, J=7.3, 3.2 Hz, 1H),1.98-1.78 (m, 2H), 1.57 (qd, J=11.5, 6.6 Hz, 1H). MS m/z 442.4 (MH+).

TABLE 1g Additional compounds prepared by the method of Example 91.Example Mass No. Structure M + H 1H NMR 92

438.3 (400 MHz, MeOD) δ ppm 7.90 (dd, J = 8.63, 5.60 Hz, 1 H) 7.36 (s, 1H) 7.12 (td, J = 8.46, 2.64 Hz, 1 H) 6.89-7.04 (m, 3 H) 6.82 (t, J =8.68 Hz, 2 H) 5.79 (dd, J = 9.90, 3.59 Hz, 1 H) 4.40- 4.56 (m, 2 H)3.87-4.00 (m, 1 H) 3.57-3.72 (m, 1 H) 2.17 (s, 3 H) 2.01-2.07 (m, 1H)1.75- 1.94 (m, 2 H) 1.25-1.38 (m, 1 H) 93

442.4 (400 MHz, MeOD) δ ppm 7.52- 7.62 (m, 1 H) 7.36-7.45 (m, 2 H)7.27-7.35 (m, 1 H) 6.97 (br dd, J = 8.46, 5.23 Hz, 2 H) 6.77- 6.90 (m, 2H) 5.65-5.76 (m, 1 H) 4.59 (br d, J = 9.39 Hz, 1 H) 4.46-4.53 (m, 1 H)3.83-3.94 (m, 1 H) 3.62-3.73 (m, 1 H) 2.02-2.14 (m, 1 H) 1.79-1.99 (m, 2H) 1.53-1.68 (m, 1 H) 94 *isolated during purification of Example 93

472.2 (400 MHz, MeOD) δ ppm 7.57- 7.68 (m, 1 H) 7.42 (br d, J = 8.31 Hz,1 H) 7.25-7.37 (m, 1 H) 6.98 (dd, J = 8.44, 5.31 Hz, 2 H) 6.78 (t, J =8.66 Hz, 2H) 5.67 (dd, J = 9.29, 3.37 Hz, 1 H) 4.44- 4.61 (m, 3 H) 4.17(d, J = 14.18 Hz, 1 H) 3.80-3.93 (m, 1 H) 3.63-3.75 (m, 1 H) 3.34 (s, 1H) 2.02-2.15 (m, 1 H)1.78- 1.98 (m, 2 H) 1.54-1.70 (m, 1 H) 95

442.4 1H NMR (400 MHz, MeOD) δppm 7.26-7.48 (m, 4 H) 6.98- 7.13 (m, 2 H)6.82-6.96 (m, 2 H) 5.88 (dd, J = 9.83, 3.57 Hz, 1 H) 4.93 (br d, J =9.98 Hz, 1 H) 4.49-4.58 (m, 1 H) 3.85-3.96 (m, 1 H) 3.60-3.70 (m, 1 H)2.01-2.09 (m, 1 H) 1.95 (dt, J = 12.20, 5.98 Hz, 1 H) 1.77- 1.89 (m, 1H)1.57 (qd, J = 11.69, 6.60 Hz, 1 H) 96

460.4 (400 MHz, DMSO-d6) δ 7.51- 7.39 (m, 2H), 7.31 (d, J = 2.8 Hz, 1H),7.24-7.04 (m, 3H), 6.84 (s, 1H), 5.75 (dd, J = 10.2, 3.7 Hz, 1H), 4.75(d, J = 10.0 Hz, 1H), 4.53-4.40 (m, 1H), 3.70 (dd, J = 11.4, 9.0 Hz,1H), 3.54 (q, J = 10.5 Hz, 1H), 1.90 (q, J = 6.7 Hz, 1H), 1.85-1.74 (m,1H), 1.67 (s, 1H), 1.25 (tq, J = 11.5, 6.2 Hz, 1H) 97

442.4 (500 MHz, CHLOROFORM-d) δ ppm 7.38 (br s, 1 H) 7.24- 7.34 (m, 1 H)7.16 (br s, 1 H) 6.97 (br s, 1 H) 6.77-6.92 (m, 3 H) 6.48 (br s, 1 H)5.37 (br 1 H) 4.44 (br s, 1 H) 4.21-4.36 (m, 1 H) 3.96 (br s, 1 H) 3.65(br s, 1 H) 2.15 (br s, 1 H) 1.97- 2.06 (m, 1 H) 1.90 (br s, 1 H)1.47-1.67 (m, 1 H) 98

424.4 (400 MHz, CDCl3) δ ppm 7.31- 7.51 (m, 6 H) 6.66-6.84 (m, 3 H) 5.44(dd, J = 9.71, 3.40 Hz, 1 H) 4.80 (d, J = 9.73 Hz, 1 H) 4.39 (br dd, J =10.10, 4.96 Hz, 1 H) 3.80-4.01 (m, 1 H) 3.56- 3.78 (m, 1 H) 1.96-2.20(m, 1 H) 1.72-1.96 (m, 2 H) 1.48- 1.72 (m, 1 H) 99

442.4 (400 MHz, CDCl3) δ ppm 7.37- 7.45 (m, 3 H) 7.14 (t, J = 8.49 Hz, 2H) 6.70-6.86 (m, 2 H) 6.66 (ddd, J = 8.75, 5.80, 2.86 Hz, 1 H) 5.39 (dd,J = 9.56, 3.50 Hz, 1 H) 4.78 (d, J = 9.54 Hz, 1 H) 4.40 (br dd, J =10.07, 4.99 Hz, 1 H) 3.82-4.02 (m, 1 H) 3.56-3.75 (m, 1 H) 2.04-2.27 (m,1 H) 1.74-1.97 (m, 2 H) 1.48-1.71 (m, 1 H) 100

460.4 (400 MHz, d-DMSO) δ ppm 7.80 (br dd, J = 11.98, 7.73 Hz, 1 H)7.28-7.47 (m, 3 H) 6.89- 7.06 (m, 3 H) 5.82 (dd, J = 10.42, 3.37 Hz, 1H) 4.86 (d, J = 10.42 Hz, 1 H) 4.48 (dt, J = 10.14, 4.93 Hz, 1 H) 3.63-3.88 (m, 1 H) 3.54 (td, J = 11.03, 7.19 Hz, 1 H) 1.75-1.92 (m, 2 H)1.51-1.75 (m, 1 H) 1.25 (qd, J = 11.64, 6.75 Hz, 1 H) 101

424.4 (500 MHz, Methanol-d4) δ 7.38 (d, J = 3.1 Hz, 1H), 7.29 (d, J =7.8 Hz, 2H), 7.16-7.05 (m, 3H), 6.97 (d, J = 5.4 Hz, 2H), 6.92 (t, J =9.2 Hz, 1H), 5.76 (dd, J = 9.2, 4.1 Hz, 1H), 4.62 (d, J = 8.7 Hz, 1H),4.57-4.49 (m, 1H), 3.90 (t, J = 10.7 Hz, 1H), 3.71 (t, J = 10.3 Hz, 1H),2.13 (s, 1H), 2.02 (d, J = 10.2 Hz, 1H), 1.90 (s, 1H), 1.69 (d, J = 11.9Hz, 1H). 102

442.2 (500 MHz, Methanol-d4) δ 7.65- 7.57 (m, 2H), 7.47 (d, J = 1.2 Hz,1H), 7.18 (t, J = 8.4 Hz, 2H), 7.11 (q, J = 8.1 Hz, 1H), 6.75 (q, J =10.5, 9.4 Hz, 2H), 5.88-5.78 (m, 1H), 4.90 (d, J = 9.8 Hz, 1H),4.61-4.51 (m, 1H), 3.96-3.84 (m, 1H), 3.66 (q, J = 10.5 Hz, 1H),2.10-2.01 (m, 1H), 1.93 (dd, J = 12.3, 6.1 Hz, 1H), 1.86 (s, 1H), 1.71-1.56 (m, 1H). 103

424.4 (500 MHz, Methanol-d4) δ 7.57 (d, J = 7.8 Hz, 2H), 7.47-7.43 (m,3H), 7.35 (d, J = 7.3 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.74 (d, J =9.7 Hz, 2H), 5.84 (d, J = 9.6 Hz, 1H), 4.90 (s, 1H), 4.55 (s, 1H), 3.90(s, 1H), 3.66 (d, J = 10.4 Hz, 1H), 2.04 (s, 1H), 1.89 (s, 2H), 1.62 (s,1H). 104

442.3 (500 MHz, Methanol-d4) δ 7.49- 7.43 (m, 2H), 7.39 (d, J = 6.5 Hz,2H), 7.10 (dt, J = 16.5, 8.0 Hz, 2H), 6.77 (q, J = 9.6, 8.8 Hz, 2H),5.85 (d, J = 10.0 Hz, 1H), 4.92 (d, J = 10.0 Hz, 1H), 4.55 (s, 1H), 3.90(t, J = 10.5 Hz, 1H), 3.66 (d, J = 9.0 Hz, 1H), 2.06 (s, 1H), 1.96 (d, J= 12.0 Hz, 1H), 1.87 (s, 1H), 1.61 (d, J = 12.2 Hz, 1H). 105

460.3 1H NMR (500 MHz, DMSO-d6) δ 7.85-7.74 (m, 1H), 7.51- 7.40 (m, 2H),7.32 (s, 1H), 7.14 (td, J = 8.7, 6.5 Hz, 1H), 7.01 (ddd, J = 11.7, 9.3,2.7 Hz, 1H), 6.90 (td, J = 8.4, 2.7 Hz, 1H), 5.85 (dd, J = 10.3, 3.6 Hz,1H), 4.86 (d, J = 10.4 Hz, 1H), 4.51 (dt, J = 10.4, 4.9 Hz, 1H), 3.78-3.69 (m, 1H), 3.62-3.53 (m, 1H), 1.92 (dt, J = 13.0, 6.9 Hz, 1H), 1.84(dt, J = 11.8, 6.0 Hz, 1H), 1.70 (h, J = 11.6 Hz, 1H), 1.31 (qd, J =11.8, 6.6 Hz, 1H).

Example 106.10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Prepared from tert-butyl 2-formylpyrrolidine-1-carboxylate by the methodof Example 32. LCMS (m/z): 424.3 (MH+), ¹H NMR (400 MHz, DMSO-d6) δ7.59-7.52 (m, 1H), 7.51-7.37 (m, 2H), 7.27 (s, 1H), 7.12 (td, J=8.2, 6.1Hz, 2H), 6.96-6.87 (m, 1H), 6.86-6.76 (m, 2H), 5.75 (dd, J=10.0, 3.6 Hz,1H), 4.72 (d, J=10.0 Hz, 1H), 4.48 (dd, J=10.3, 5.3 Hz, 1H), 3.79-3.68(m, 1H), 3.66-3.54 (m, 1H), 1.96-1.86 (m, 1H), 1.85-1.61 (m, 2H), 1.36(td, J=11.3, 6.5 Hz, 1H).

Example 107.4-((R)-(3-fluorophenyl)((9aR,10S)-4-hydroxy-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-10-yl)methyl)benzonitrile

Step 1: (R)-tert-butyl2-((1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate

Added (R)-tert-butyl2-((1R,2R)-2-(4-chlorophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (190 mg, 0.362 mmol, prepared by the generalmethod of AA-1), Zn powder (23.67 mg, 0.362 mmol), zinc cyanide (85 mg,0.724 mmol), rac-2-(di-t-butylphosphino)-1,1′-binapthyl (28.8 mg, 0.072mmol) and bis(2,2,2-trifluoroacetyl)palladium (10.88 mg, 0.036 mmol) atRT to a microwave vial equipped with a stir bar. Cap was sealed and N₂was passed through for 5 min. DMA (Volume: 4 mL) was added through thesyringe and N₂ was passed through for an additional 5 min. The microwavevial was placed in a heating block and heated at 95° C. for 1H. Thereaction mixture was diluted with DCM and filtered through celite. Thecelite was washed with DCM and the filtrate was concentrated. Silica gelcolumn chromatography (EtOAc/heptane) provided (R)-tert-butyl2-((1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate,(110 mg) in 74% yield. MS m/z 411.2 (MH+).

Step 2: (R)-tert-butyl2-((1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate

To a solution of (R)-tert-butyl2-((1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate(110 mg, 0.268 mmol) in pyridine (4 mL) at 0° C. was addedmethanesulfonyl chloride (0.251 mL, 3.22 mmol). After 5 min the ice bathwas removed and the reaction was stirred for 2 h at RT. The reactionmixture was then partitioned between DCM and water. The DCM layer waswashed with sat'd aq. NaHCO₃ then brine, dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/heptane) provided(R)-tert-butyl2-((1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate (105 mg) in 80% yield. MS m/z 489.3(MH+).

Step 3:(1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1-((R)-pyrrolidin-2-yl)ethylMethanesulfonate Hydrochloride

Added HCl (4.0 M in dioxane, 2 ml, 8 mmol) to (R)-tert-butyl2-((1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate(105 mg, 0.215 mmol). Stirred for 1H at RT. The reaction was thenconcentrated to give(1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1-((R)-pyrrolidin-2-yl)ethylmethanesulfonate hydrochloride, which was used in the next step withoutfurther purification. MS m/z 389.3 (MH+).

Step 4:(1R,2R)-1-((R)-1-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(4-cyanophenyl)-2-(3-fluorophenyl)ethylMethanesulfonate

Added Huenig's base (0.142 mL, 0.812 mmol) and HATU (100 mg, 0.264 mmol)to a solution of5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylicacid (84 mg, 0.223 mmol: see US 2015/0072982 A1) in DCM (1 mL) at RT.Stirred at RT for 15 min, then added a solution of crude(1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1-((R)-pyrrolidin-2-yl)ethylmethanesulfonate hydrochloride (83 mg, 0.203 mmol) in DCM (1 mL) and 2equiv of Huenig's base. The mixture was stirred at RT for 1H. Thereaction was then diluted with DCM and washed with water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Silicagel column chromatography (EtOAc/EtOH/heptane) provided(1R,2R)-1-((R)-1-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(4-cyanophenyl)-2-(3-fluorophenyl)ethylmethanesulfonate (130 mg) in 86% yield. MS m/z 747.4 (MH+).

Step 5:(1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)ethylMethanesulfonate

A solution of(1R,2R)-1-((R)-1-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(4-cyanophenyl)-2-(3-fluorophenyl)ethylmethanesulfonate (70 mg, 0.094 mmol) in methanol (5 mL) was purged withnitrogen. Added 10% palladium on carbon (29.9 mg, 0.028 mmol) andattached a hydrogen balloon. The flask was evacuated and refilled withhydrogen (3 times) and then stirred vigorously for 1 h at RT under aballoon of hydrogen. The reaction mixture was filtered through celiteand the filter cake was washed with MeOH. The filtrate was concentratedto provide crude(1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)ethylmethanesulfonate which was used in the next step without furtherpurification. MS m/z 657.4 (MH+).

Step 6:(1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)ethylMethanesulfonate

To crude(1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)ethylmethanesulfonate (61 mg, 0.088 mmol) was added TFA (1.2 ml, 15.58 mmol).The reaction mixture was stirred 2H at RT. The solvent was concentratedand the residue was azeotroped with toluene to provide crude(1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)ethylmethanesulfonate which was used in the next step without furtherpurification. MS m/z 527.3 (MH+).

Step 7:4-((R)-(3-fluorophenyl)((9aR,10S)-4-hydroxy-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-10-yl)methyl)benzonitrile

To a solution of crude(1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)ethylmethanesulfonate (49 mg, 0.084 mmol) in DMF (2 mL) was added potassiumcarbonate (46.3 mg, 0.335 mmol) and the mixture was stirred overnight atRT. The reaction was filtered through a 1 micron filter and purified byreverse phase HPLC. Product fractions were combined, frozen andlyophilized to afford a TFA salt of4-((R)-(3-fluorophenyl)((9aR,10S)-4-hydroxy-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-10-yl)methyl)benzonitrile(15.2 mg, 0.027 mmol, white solid) in 32.7% yield over three steps. ¹HNMR (400 MHz, CD₃OD) δ ppm 7.36-7.53 (m, 5H) 7.22 (d, J=8.27 Hz, 2H)7.00-7.14 (m, 1H) 5.83 (dd, J=9.93, 3.62 Hz, 1H) 4.72 (d, J=9.93 Hz, 1H)4.46-4.59 (m, 1H) 3.78-3.94 (m, 1H) 3.68 (td, J=11.09, 7.51 Hz, 1H)1.99-2.11 (m, 1H) 1.73-1.96 (m, 2H) 1.49-1.65 (m, 1H). MS m/z 431.2(MH+).

Example 108.(9aR,10S)-10-((S)-(4-chlorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Step 1:5-(benzyloxy)-3-((R)-2-((1R,2R)-2-(4-chlorophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(1H)-one

Added Huenig's base (0.360 mL, 2.064 mmol) and HATU (255 mg, 0.671 mmol)to a solution of5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylicacid (214 mg, 0.568 mmol: see US 2015/0072982 A1) in DCM (3 mL) at RT.Stirred at RT for 15 min, then added a solution of crude(1R,2R)-2-(4-chlorophenyl)-2-(3-fluorophenyl)-1-((R)-pyrrolidin-2-yl)ethanol(165 mg, 0.516 mmol, prepared by the method of Example 51, steps 1-3) inDCM (3 mL) and 2 equiv of Huenig's base. The mixture was stirred at RTfor 1 h. The reaction was then diluted with DCM and washed with waterand brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/EtOH/heptane)provided5-(benzyloxy)-3-((R)-2-((1R,2R)-2-(4-chlorophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(1H)-one(280 mg) in 80% yield. MS m/z 678.6 (MH+).

Step 2:(1R,2S)-1-((R)-1-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)-2-(3-fluorophenyl)ethylMethanesulfonate

To a solution of5-(benzyloxy)-3-((R)-2-((1R,2R)-2-(4-chlorophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(1H)-one(280 mg, 0.413 mmol) in 2,6-lutidine (4 mL) at 0° C. was addedmethanesulfonyl chloride (0.643 mL, 8.26 mmol). After 5 min the ice bathwas removed and the reaction was stirred for 3 h at RT. The reactionmixture was then partitioned between DCM and water. The DCM layer wasseparated and washed with 1N HCl, saturated aqueous NaHCO₃, brine, driedover Na₂SO₄, filtered and concentrated. Silica gel column chromatography(EtOAc/EtOH/heptane) provided(1R,2S)-1-((R)-1-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)-2-(3-fluorophenyl)ethylmethanesulfonate (280 mg) in 90% yield. MS m/z 756.6 (MH+).

Step 3:(1R,2S)-2-(4-chlorophenyl)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)ethylMethanesulfonate

To(1R,2S)-1-((R)-1-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)-2-(3-fluorophenyl)ethylmethanesulfonate (240 mg, 0.286 mmol) was added TFA (4 mL, 51.9 mmol).The reaction mixture was stirred 1 h at RT then heated for 20 min at 80°C. in a microwave reactor. The solvent was concentrated and the residuewas azeotroped with toluene to provide crude(1R,2S)-2-(4-chlorophenyl)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)ethylmethanesulfonate which was used in the next step without furtherpurification. MS m/z 536.2 (MH+).

Step 4:(9aR,10S)-10-((S)-(4-chlorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

To a solution of crude(1R,2S)-2-(4-chlorophenyl)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)ethylmethanesulfonate (175 mg, 0.327 mmol) in DMF (6 mL) was added potassiumcarbonate (181 mg, 1.306 mmol) and the mixture was stirred overnight atRT. The reaction was filtered through a 1 micron filter and purified byreverse phase HPLC. Product fractions were combined, frozen andlyophilized to afford a formate salt of(9aR,10S)-10-((S)-(4-chlorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione(33.5 mg, 0.068 mmol, white solid) in 29% yield. ¹H NMR (400 MHz, CD₃OD)δ ppm 7.57 (d, J=8.46 Hz, 2H) 7.35-7.48 (m, 3H) 7.02-7.13 (m, 1H)6.78-6.86 (m, 1H) 6.68-6.77 (m, 2H) 5.74 (dd, J=9.59, 3.52 Hz, 1H) 4.60(d, J=9.59 Hz, 1H) 4.50 (br dd, J=10.47, 5.18 Hz, 1H) 3.82-3.94 (m, 1H)3.67 (td, J=11.00, 7.58 Hz, 1H) 2.01-2.13 (m, 1H) 1.75-1.97 (m, 2H)1.51-1.64 (m, 1H)

MS m/z 440.3 (MH+).

TABLE 1h Additional compounds prepared by the method of Example 108.Example Mass No. Structure M + H 1H NMR 109

440.4 (400 MHz, MeOD) δppm 7.62 (s, 1 H) 7.55 (d, J = 7.78 Hz, 1 H)7.37- 7.46 (m, 2 H) 7.30-7.37 (m, 1 H) 7.03-7.17 (m, 1 H) 6.64-6.91(m, 3H) 5.78 (dd, J = 9.54, 3.62 Hz, 1 H) 4.61 (d, J = 9.54 Hz, 1 H) 4.51(dt, J = 10.26, 4.97 Hz, 1 H) 3.78- 3.95 (m, 1 H) 3.68 (td, J = 11.09,7.51 Hz, 1H) 2.00-2.11 (m, 1 H) 1.79-1.97 (m, 2 H) 1.50- 1.70 (m, 1 H)110

484.1 (500 MHz, CD3OD) δ ppm 7.58 (s, 2H), 7.33 (s, 3H), 7.15 (t, J =7.6 Hz, 3H), 6.98 (d, J = 6.6 Hz, 1H), 5.85 (d, J = 10.0 Hz, 1H), 5.33(d, J = 10.3 Hz, 1H), 4.54 (s, 1H), 3.90 (t, J = 9.9 Hz, 1H), 3.69-3.57(m, 1H), 2.02 (s, 1H), 1.91 (d, J = 6.0 Hz, 1H), 1.85 (d, J = 9.3 Hz,1H), 1.60-1.48 (m, 1H)

Example 111.(9aR,10S)-10-((R)-(2-bromophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione

Prepared by the method of Example 107 (steps 2-4) and Example 108 (steps3-4). LCMS (m/z): 484.1 (MH+), 1H NMR (500 MHz, CD₃OD) 5 ppm 8.07 (d,J=7.7 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.27(d, J=7.7 Hz, 1H), 7.03 (s, 2H), 6.83 (t, J=8.3 Hz, 2H), 5.78 (d, J=9.4Hz, 1H), 4.90 (d, J=9.6 Hz, 1H), 4.52 (s, 1H), 3.94 (s, 1H), 3.67 (s,1H), 2.07 (s, 1H), 1.89 (s, 2H), 1.38 (s, 1H).

Example 112.(9aR,10S)-10-((S)-(3-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Step 1:(1R,2S)-2-(3-fluorophenyl)-1-((R)-1-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(o-tolyl)ethylMethanesulfonate

Added Huenig's base (0.102 mL, 0.583 mmol) and HATU (72 mg, 0.189 mmol)to a solution of4-oxo-5-((2-(trimethylsilyl)ethoxy)methoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylicacid (66.8 mg, 0.160 mmol: see US 2015/0072982 A1) in DCM (1 mL) at RT.Stirred at RT for 15 min, then added a solution of crude(1R,2S)-2-(3-fluorophenyl)-1-((R)-pyrrolidin-2-yl)-2-(o-tolyl)ethylmethanesulfonate (55 mg, 0.146 mmol, prepared by the method of Example32, steps 1-2) in DCM (1 mL) and 2 equiv of Huenig's base. The mixturewas stirred at RT for 1 h. The reaction was then diluted with DCM andwashed with water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. Silica gel column chromatography(EtOAc/EtOH/heptane) provided(1R,2S)-2-(3-fluorophenyl)-1-((R)-1-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(o-tolyl)ethylmethanesulfonate (48 mg) in 42% yield. MS m/z 776.5 (MH+).

Step 2:(1R,2S)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(o-tolyl)ethylMethanesulfonate

To(1R,2S)-2-(3-fluorophenyl)-1-((R)-1-(4-oxo-5-((2-(trimethylsilyl)ethoxy)methoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(o-tolyl)ethylmethanesulfonate (48 mg, 0.062 mmol) was added TFA (1.2 mL, 15.6 mmol).The reaction mixture was stirred 1.5 hr at RT. The solvent wasconcentrated and the residue was azeotroped with toluene to providecrude(1R,2S)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(o-tolyl)ethylmethanesulfonate which was used in the next step without furtherpurification. MS m/z 516.3 (MH+).

Step 3:(9aR,10S)-10-((S)-(3-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

To a solution of crude(1R,2S)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(o-tolyl)ethylmethanesulfonate (32 mg, 0.062 mmol) in DMF (1 mL) was added potassiumcarbonate (30 mg, 0.217 mmol) and the mixture was stirred overnight atRT. The reaction was filtered through a 1 micron filter and purified byreverse phase HPLC. Product fractions were combined, frozen andlyophilized to afford a TFA salt of(9aR,10S)-10-((S)-(3-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione(3 mg, 0.005 mmol, white solid) in 21% yield over two steps. 1H NMR (400MHz, MeOD) 5 ppm 1.49-1.68 (m, 1H) 1.76-2.11 (m, 4H) 2.14-2.39 (m, 3H)3.66 (td, J=11.36, 7.12 Hz, 1H) 3.80-3.96 (m, 1H) 4.46-4.64 (m, 1H)5.74-6.02 (m, 1H) 6.84-7.09 (m, 4H) 7.16 (br s, 1H) 7.25-7.55 (m, 4H),MS m/z 420.3 (MH+).

TABLE 1i Additional compounds prepared by the method of Example 112.Example Mass No. Structure M + H 1H NMR 113

440.3 (400 MHz, MeOD) δ ppm 1.53- 1.68 (m, 1 H) 1.75-1.97 (m, 2 H)2.03-2.12 (m, 1 H) 3.68 (td, J = 11.11, 7.46 Hz, 1 H) 3.81-3.95 (m, 1H)4.44-4.55 (m, 1 H) 4.61 (d, J = 9.54 Hz, 1 H) 5.76 (dd, J = 9.54, 3.62Hz, 1 H) 6.90 (br d, J = 6.99 Hz, 1 H) 6.99 (s, 1 H) 7.01-7.14 (m, 3 H)7.30-7.53 (m, 4 H) 114

440.3 (400 MHz, MeOD) δ ppm 1.55- 1.68 (m, 1 H) 1.80-1.99 (m, 2 H)2.02-2.12 (m, 1 H) 3.62-3.75 (m, 1 H) 3.82-3.92 (m, 1 H) 4.46- 4.64 (m,2 H) 5.76 (dd, J = 9.49, 3.57 Hz, 1 H) 6.82 (t, J = 8.68 Hz, 2 H) 6.98(dd, J = 8.53, 5.31 Hz, 2 H) 7.29-7.35 (m, 1 H) 7.37-7.46 (m, 2 H)7.54(br d, J = 7.68 Hz, 1 H) 7.61 (s, 1 H)

Example 115.(9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Step 1: Tert-butyl(R)-5-(hydroxymethyl)-2,2-dimethylpyrrolidine-1-carboxylate

Borane tetrahydrofuran complex (1M in THF) (15.41 ml, 15.41 mmol) wasadded dropwise to a 0° C. solution of(R)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidine-2-carboxylic acid(2.2 g, 9.04 mmol) in THF under an atmosphere of nitrogen, and themixture was stirred at RT for 3 hours. The solution was cooled, 2.5 mLof water was added, then sodium carbonate (1.960 g, 18.50 mmol), and themixture stirred vigorously at RT for 30 minutes. The mixture wasextracted with ethyl acetate, washed with brine, dried with Na₂SO₄, andconcentrated to provide tert-butyl(R)-5-(hydroxymethyl)-2,2-dimethylpyrrolidine-1-carboxylate (2.1 g, >99%yield) as a colorless oil, which was used in the next step withoutfurther purification. LCMS [MH+] 230.1/0.91 min.

Step 2: tert-butyl (R)-5-formyl-2,2-dimethylpyrrolidine-1-carboxylate

DMSO (1.431 ml, 20.15 mmol) was added dropwise to a −78° C. solution ofoxalyl chloride (0.942 ml, 10.99 mmol) in DCM (Volume: 41.6 ml, Ratio:10), and the solution was stirred for 15 minutes. A solution oftert-butyl (R)-5-(hydroxymethyl)-2,2-dimethylpyrrolidine-1-carboxylatein DCM (Volume: 4.16 ml, Ratio: 1.000) was then added, and the solutionstirred for 1 hour at −78° C. DIPEA (6.40 ml, 36.6 mmol) was then added,and the solution was warmed to room temperature. The mixture was thenwashed sequentially with 1M HCl, water, then brine, dried with Na₂SO₄,and concentrated to give tert-butyl(R)-5-formyl-2,2-dimethylpyrrolidine-1-carboxylate (1.9 g, 91% yield) asa yellow oil, which was used in the next step without furtherpurification. LCMS [MH+] 228.2/0.82 min.

Example 115:(9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Prepared from tert-butyl(R)-5-formyl-2,2-dimethylpyrrolidine-1-carboxylate by the method ofExample 32. LCMS (m/z): 452.3 (MH+), 1H NMR (500 MHz, CD₃OD) 5 ppm 7.45(q, J=7.8 Hz, 1H), 7.41-7.34 (m, 3H), 7.06 (t, J=8.1 Hz, 1H), 7.04-6.98(m, 2H), 6.82 (t, J=8.5 Hz, 2H), 5.70 (d, J=10.1 Hz, 1H), 4.67-4.58 (m,1H), 4.42 (d, J=9.9 Hz, 1H), 1.89-1.79 (m, 2H), 1.75 (d, J=12.3 Hz, 1H),1.69 (s, 3H), 1.63 (s, 3H), 1.60-1.50 (m, 1H).

Example 116.(9aR,10R)-10-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Prepared from tert-butyl(R)-5-formyl-2,2-dimethylpyrrolidine-1-carboxylate by the method ofExample 32. LCMS (m/z): 452.3 (MH+), ¹H NMR (500 MHz, CD₃OD) δ ppm 7.66(s, 1H), 7.41-7.35 (m, 2H), 7.29 (d, J=6.8 Hz, 1H), 7.08 (t, J=8.5 Hz,3H), 6.99 (d, J=10.7 Hz, 1H), 6.95 (s, 1H), 5.32 (dd, J=11.3, 3.9 Hz,1H), 5.09 (d, J=3.8 Hz, 1H), 4.13 (d, J=6.5 Hz, 1H), 1.93 (q, J=9.9, 8.9Hz, 1H), 1.86 (d, J=6.4 Hz, 2H), 1.82 (s, 1H), 1.63 (s, 3H), 1.56 (s,3H).

Example 117.(7S,9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dionetert-butyl (2R,5S)-2-formyl-5-methylpyrrolidine-1-carboxylate

Prepared from tert-butyl(2R,5S)-2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate by themethod of Example 115, Step 2. LCMS [M+Na]+236.2/0.70 min.

Example 117:(7S,9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Prepared from tert-butyl(2R,5S)-2-formyl-5-methylpyrrolidine-1-carboxylate by the method ofExample 32. LCMS (m/z): 438.5 (MH+), 1H NMR (500 MHz, CD₃OD) δ ppm7.47-7.37 (m, 4H), 7.07-7.02 (m, 1H), 7.00 (dd, J=8.7, 5.3 Hz, 2H), 6.81(t, J=8.7 Hz, 2H), 5.70 (dd, J=9.5, 3.9 Hz, 1H), 4.69-4.63 (m, 1H), 4.56(d, J=9.5 Hz, 1H), 4.41 (q, J=6.4 Hz, 1H), 2.26-2.18 (m, 1H), 1.95-1.88(m, 1H), 1.63-1.55 (m, 2H), 1.48 (d, J=6.3 Hz, 3H).

Example 118.(7S,9aR,10R)-10-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione

Prepared from tert-butyl(2R,5S)-2-formyl-5-methylpyrrolidine-1-carboxylate by the method ofExample 32. LCMS (m/z): 438.4 (MH+), 1H NMR (500 MHz, CD₃OD) δ ppm 7.61(s, 1H), 7.37 (dd, J=8.0, 5.5 Hz, 2H), 7.31 (d, J=6.8 Hz, 1H), 7.10 (d,J=7.8 Hz, 1H), 7.07 (t, J=8.6 Hz, 2H), 7.04-6.94 (m, 2H), 5.37 (dd,J=9.8, 5.8 Hz, 1H), 5.05 (d, J=5.7 Hz, 1H), 4.29 (h, J=6.5 Hz, 1H), 4.10(td, J=10.1, 5.6 Hz, 1H), 2.27 (dd, J=13.1, 7.2 Hz, 1H), 1.78-1.71 (m,1H), 1.68 (dd, J=11.2, 8.0 Hz, 1H), 1.51 (ddd, J=19.7, 11.8, 7.8 Hz,1H), 1.39 (d, J=6.3 Hz, 3H).

Example 119.(7R,9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione

Prepared from tert-butyl(2R,5R)-2-formyl-5-methylpyrrolidine-1-carboxylate (For synthesis see US20120195857, using tert-butyl(2R,5R)-2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate) by themethod of Example 32. LCMS (m/z): 438.4 (MH+), 1H NMR (500 MHz, CD₃OD) δppm 7.46 (q, J=7.7 Hz, 1H), 7.40 (d, J=8.7 Hz, 2H), 7.38 (s, 1H), 7.08(s, 1H), 7.05-6.95 (m, 2H), 6.84 (t, J=8.5 Hz, 2H), 5.74 (dd, J=10.2,3.1 Hz, 1H), 4.51 (dd, J=7.4, 4.6 Hz, 1H), 4.47-4.36 (m, 2H), 2.01 (dd,J=13.3, 6.4 Hz, 1H), 1.86-1.75 (m, 1H), 1.68 (dd, J=12.5, 6.3 Hz, 1H),1.57 (dd, J=12.6, 6.3 Hz, 1H), 1.46 (d, J=6.5 Hz, 3H).

Example 120.(7R,9aR,10R)-10-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione

Prepared from tert-butyl(2R,5R)-2-formyl-5-methylpyrrolidine-1-carboxylate (For synthesis see US20120195857, using tert-butyl(2R,5R)-2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate) by themethod of Example 32. LCMS (m/z): 438.4 (MH+), 1H NMR (500 MHz, CD₃OD) δppm 7.70 (s, 1H), 7.37 (dd, J=8.7, 5.3 Hz, 2H), 7.30 (td, J=8.0, 6.2 Hz,1H), 7.12 (d, J=7.8 Hz, 1H), 7.08 (t, J=8.7 Hz, 2H), 7.03 (d, J=10.6 Hz,1H), 6.96 (td, J=8.4, 2.3 Hz, 1H), 5.36 (dd, J=11.4, 4.6 Hz, 1H), 5.15(d, J=4.5 Hz, 1H), 4.37-4.26 (m, 1H), 4.08 (d, J=5.4 Hz, 1H), 2.07-1.96(m, 1H), 1.91 (dd, J=11.6, 6.2 Hz, 1H), 1.87-1.80 (m, 1H), 1.73 (dd,J=12.3, 6.0 Hz, 1H), 1.38 (d, J=6.5 Hz, 3H).

Example 121.(8S,9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8-methoxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione

Prepared from tert-butyl(2R,4S)-2-formyl-4-methoxypyrrolidine-1-carboxylate (For synthesis seeWO 2014046441 A1, using tert-butyl(2R,4S)-2-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate) by themethod of Example 32. LCMS (m/z): 454.3 (MH+), ¹H NMR (500 MHz, CD₃OD) δppm 7.49-7.43 (m, 1H), 7.43-7.34 (m, 3H), 7.12-7.04 (m, 2H), 6.82 (td,J=8.5, 2.2 Hz, 1H), 6.80-6.73 (m, 2H), 5.78 (dd, J=9.8, 3.6 Hz, 1H),4.71 (dt, J=11.9, 4.6 Hz, 1H), 4.62 (d, J=9.8 Hz, 1H), 4.06 (t, J=3.8Hz, 1H), 3.90 (d, J=13.5 Hz, 1H), 3.83 (dd, J=13.5, 3.9 Hz, 1H), 3.30(s, 3H), 2.08 (dd, J=13.3, 5.3 Hz, 1H), 1.62 (td, J=12.9, 4.0 Hz, 1H).

Example 122.(8R,9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8-methoxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Prepared from tert-butyl(2R,4R)-2-formyl-4-methoxypyrrolidine-1-carboxylate (For synthesis seeWO 2014046441 A1, using tert-butyl(2R,4R)-2-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate) by themethod of Example 32. LCMS (m/z): 454.3 (MH+), 1H NMR (500 MHz, CD₃OD) δppm 7.53 (s, 1H), 7.48-7.35 (m, 3H), 7.06 (t, J=7.1 Hz, 2H), 6.79 (dd,J=15.8, 8.3 Hz, 2H), 6.72 (d, J=10.1 Hz, 1H), 5.67 (s, 1H), 4.91 (d,J=8.0 Hz, 1H), 4.60 (s, 1H), 4.13 (d, J=5.3 Hz, 1H), 3.87 (s, 1H),3.85-3.79 (m, 1H), 3.37 (s, 3H), 2.42-2.31 (m, 1H), 1.80 (s, 1H).

Example 123.(10aR,11S)-11-benzhydryl-4-hydroxy-7,8,10a,11-tetrahydro-10H-pyridazino[1′,6′:4,5]pyrazino[2,1-c][1,4]oxazine-3,5-dione

Prepared from tert-butyl (S)-3-formylmorpholine-4-carboxylate by themethod of Example 32. LCMS (m/z): 404.2 (MH+), 1H NMR (500 MHz, DMSO-d6)δ 7.61-7.55 (m, 2H), 7.39 (t, J=7.7 Hz, 2H), 7.29 (t, J=7.5 Hz, 1H),7.21 (dd, J=7.8, 1.8 Hz, 2H), 7.17 (s, 1H), 7.17-7.10 (m, 3H), 5.50 (d,J=11.1 Hz, 1H), 4.58 (d, J=11.1 Hz, 1H), 4.37 (s, 1H), 3.98 (d, J=9.0Hz, 1H), 3.75-3.66 (m, 3H), 3.48 (s, 1H), 3.02-2.95 (m, 1H).

Examples 124A and 124B

Step 1: Tert-butyl2-(1-hydroxy-2,2-diphenylethyl)piperidine-1-carboxylate

A solution of BuLi (2.5 M in hexanes) (6.47 mL, 16.18 mmol) was added toa solution of diphenylmethane (2.86 g, 16.99 mmol) in THF (Volume: 35mL) in a dropwise fashion at RT. The resulting solution turned red andwas stirred for an additional 10 minutes. The solution was titrated intoa solution of tert-butyl 2-formylpiperidine-1-carboxylate (3.45 g, 16.18mmol) in THF (Volume: 21 mL) by syringe at −78° C. The reaction wasstirred for 15 minutes after which it was complete by LCMS. The reactionwas quenched by the addition of saturated aqueous ammonium chloridesolution. The aqueous layer was extracted with diethyl ether (3×), thecombined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated. Silica gel column chromatography(EtOAc/heptane) provided tert-butyl2-(1-hydroxy-2,2-diphenylethyl)piperidine-1-carboxylate (2.80 g) in 45%yield. MS m/z 382.4 (MH⁺).

Step 2: Tert-butyl 2-(2,2-diphenylacetyl)piperidine-1-carboxylate

To a solution of tert-butyl2-(1-hydroxy-2,2-diphenylethyl)piperidine-1-carboxylate (2.80 g, 7.34mmol) in DCM (volume: 73.4 mL) was added Dess-Martin periodinane (DMP)(6.23 g, 14.68 mmol) at 5-10° C. The reaction mixture was stirred for 4h at RT. After completion of the reaction, it was quenched with aqueoussodium sulfite (20 mL) and stirred for 1 h. The product was thenextracted with dichloromethane (2×20 mL). The combined organic layer waswashed with water (20 mL) and concentrated. Silica gel chromatography(EtOAc/heptane) provided tert-butyl2-(2,2-diphenylacetyl)piperidine-1-carboxylate (1.76 g) in 63% yield. MSm/z 380.4 (MH⁺).

Step 3: 2,2-diphenyl-1-(piperidin-2-yl)ethanone

A solution of hydrochloric acid (4.0 M in dioxane) (23.19 ml, 93 mmol)was added to tert-butyl 2-(2,2-diphenylacetyl)piperidine-1-carboxylate(1.76 g, 4.64 mmol), and was stirred at room temperature for 1.5 hours.The mixture was then concentrated and placed under high vacuum overnightto provide a hydrochloride salt of2,2-diphenyl-1-(piperidin-2-yl)ethanone (1.37 g, white powder) in 94%yield. MS m/z 280.3 (MH⁺).

Step 4:3-(2-(2,2-diphenylacetyl)piperidine-1-carbonyl)-5-((2-(trimethylsilyl)ethoxy)methoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(1H)-one

DIPEA (4.27 mL, 24.52 mmol) and HATU (2.424 g, 6.37 mmol) were added toa solution of4-oxo-5-((2-(trimethylsilyl)ethoxy)methoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylicacid (2.247 g, 5.39 mmol: see US 2015/0072982 A1) in DCM (volume: 50 mL)at RT. The mixture was stirred at RT for 15 min, then added a solutionof crude 2,2-diphenyl-1-(piperidin-2-yl)ethanone hydrochloride (1.37 g,4.90 mmol) and DIPEA (2 mL) in DCM (Volume: 25). The mixture was stirredat RT overnight before it was diluted with DCM and washed with water andbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (EtOAc/heptane/MeOH)provided3-(2-(2,2-diphenylacetyl)piperidine-1-carbonyl)-5-((2-(trimethylsilyl)ethoxy)methoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(1H)-one(1.85 g) in 56% yield. MS m/z 678.5 (MH⁺).

Step 5:3-(2-(2,2-diphenylacetyl)piperidine-1-carbonyl)-5-hydroxypyridazin-4(1H)-one

A solution of3-(2-(2,2-diphenylacetyl)piperidine-1-carbonyl)-5-((2-(trimethylsilyl)ethoxy)methoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(1H)-one (83.4mg, 0.123 mmol) in TFA (1.5 ml, 19.47 mmol) was stirred at rt for 2days. The reaction was concentrated and the residue was azeotroped frombenzene (3×) to provide crude3-(2-(2,2-diphenylacetyl)piperidine-1-carbonyl)-5-hydroxypyridazin-4(1H)-oneyield (51 mg) that was used in the next step without purification. MSm/z 418.3 (MH⁺).

Step6:11-(diphenylmethylene)-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dioneand11-benzhydryl-4-hydroxy-7,8,9,10-tetrahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

To a solution of3-(2-(2,2-diphenylacetyl)piperidine-1-carbonyl)-5-hydroxypyridazin-4(1H)-one(867 mg, 2.077 mmol) in 1,4-dioxane (Volume: 29.7 ml) was addedconcentrated sulfuric acid (221 μl, 4.15 mmol). The mixture was heatedto 115° C. for 90 min in a microwave reactor. The reaction was filteredand the filtrate was purified by reverse phase HPLC. Product fractionswere combined, frozen and lyophilized to afford11-(diphenylmethylene)-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione(Peak 1, MS m/z 400.3 (MH⁺)) and11-benzhydryl-4-hydroxy-7,8,9,10-tetrahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione(Peak 2, MS m/z 400.3 (MH⁺)).

Step 7A:11-benzhydryl-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

To a solution of11-(diphenylmethylene)-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione(22.8 mg, 0.044 mmol) in MeOH (Volume: 1 mL) were added palladiumhydroxide on carbon (20%) (31.2 mg, 0.044 mmol) and ammonium formate(28.0 mg, 0.444 mmol). The vial was sealed and the reaction was heatedto 70° C. for 2 h. The reaction was filtered through celite and thefiltrate was concentrated. The residue was dissolved in DMF and purifiedby reverse phase HLPC. Product fractions were combined, frozen andlyophilized to afford a TFA salt of11-benzhydryl-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione(4.1 mg, white solid) in 17% yield. ¹H NMR (500 MHz, Methanol-d₄) δ7.65-7.55 (m, 2H), 7.51 (s, 1H), 7.40 (t, J=7.8 Hz, 2H), 7.33-7.26 (m,1H), 7.05 (s, 6H), 5.58 (dd, J=8.0, 3.1 Hz, 1H), 4.79 (d, J=8.0 Hz, 1H),4.40 (d, J=13.8 Hz, 1H), 4.18 (d, J=9.6 Hz, 1H), 3.15-3.06 (m, 1H), 1.89(d, J=13.6 Hz, 1H), 1.83-1.75 (m, 1H), 1.70-1.61 (m, 2H), 1.51 (qd,J=12.9, 3.9 Hz, 1H), 1.37 (tt, J=12.2, 3.6 Hz, 1H). MS m/z 402.2 (MH⁺).

Step 7B:11-benzhydryl-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

To a solution of11-benzhydryl-4-hydroxy-7,8,9,10-tetrahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione(8.3 mg, 0.016 mmol) in MeOH (1 mL) were added palladium hydroxide oncarbon (20%) (11.35 mg, 0.016 mmol) and ammonium formate (10.19 mg,0.162 mmol). The vial was sealed and the reaction was heated to 70° C.for 2 h. The reaction was filtered through celite and the filtrate wasconcentrated. The residue was dissolved in DMF and purified by reversephase HLPC. Product fractions were combined, frozen and lyophilized toafford a TFA salt of11-benzhydryl-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione(1.5 mg) in 17% yield. ¹H NMR (500 MHz, Methanol-d₄) δ 7.53-7.49 (m,2H), 7.41 (t, J=7.7 Hz, 2H), 7.35 (s, 1H), 7.34-7.30 (m, 1H), 7.15 (tt,J=5.5, 2.6 Hz, 5H), 5.37-5.27 (m, 1H), 4.62 (s, 1H), 4.48 (d, J=11.1 Hz,1H), 3.69 (d, J=11.4 Hz, 1H), 2.81-2.67 (m, 1H), 1.92 (d, J=18.0 Hz,2H), 1.70-1.49 (m, 4H). MS m/z 402.1 (MH+).

Example 125A.11-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Prepared from bis(3-fluorophenyl)methane by the method of Example 124A.LCMS (m/z): 438.0 (MH+), 1H NMR (500 MHz, Methanol-d4) δ 7.51-7.44 (m,1H), 7.42 (s, 1H), 7.38 (d, J=7.7 Hz, 2H), 7.22-7.15 (m, 1H), 7.11 (d,J=7.9 Hz, 1H), 7.05 (d, J=10.2 Hz, 1H), 6.99 (d, J=7.9 Hz, 1H),6.95-6.89 (m, 1H), 5.39 (d, J=11.3 Hz, 1H), 4.67 (s, 1H), 4.62 (d,J=11.2 Hz, 1H), 3.67 (d, J=10.2 Hz, 1H), 2.75 (d, J=12.2 Hz, 1H), 1.94(s, 1H), 1.67 (q, J=11.7, 10.0 Hz, 4H).

Example 125B.11-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Prepared from bis(3-fluorophenyl)methane by the method of Example 124B.LCMS (m/z): 438.0 (MH+), 1H NMR (500 MHz, Methanol-d4) δ 8.22 (d, J=20.2Hz, 1H), 7.58 (s, 1H), 7.48-7.40 (m, 2H), 7.38-7.33 (m, 2H), 7.32-7.23(m, 3H), 5.63 (d, J=7.7 Hz, 1H), 4.91 (d, J=8.2 Hz, 1H), 4.42 (d, J=14.3Hz, 1H), 4.13 (t, J=6.4 Hz, 2H), 3.15-3.06 (m, 1H), 7.38-7.33 (m, 1H),1.76-1.60 (m, 4H).

Example 126.11-benzhydryl-4-hydroxy-7,8,10a,11-tetrahydro-10H-pyridazino[1′,6′:4,5]pyrazino[2,1-c][1,4]oxazine-3,5-dione

Prepared from tert-butyl 3-formylmorpholine-4-carboxylate by the methodof Example 124A. LCMS (m/z): 404.2 (MH+), 1H NMR (500 MHz, Methanol-d4)δ 7.58 (d, J=7.4 Hz, 2H), 7.43 (t, J=7.7 Hz, 2H), 7.37 (s, 1H), 7.31 (t,J=7.4 Hz, 1H), 7.06-7.01 (m, 3H), 6.99 (dd, J=6.8, 3.0 Hz, 2H), 5.61(dd, J=8.9, 3.4 Hz, 1H), 4.81 (d, J=8.9 Hz, 1H), 4.47 (dt, J=11.2, 3.9Hz, 1H), 4.24 (dd, J=13.9, 3.0 Hz, 1H), 4.04 (dd, J=11.9, 4.7 Hz, 1H),3.63 (td, J=11.9, 3.6 Hz, 2H), 3.25 (d, J=11.5 Hz, 1H), 3.23-3.17 (m,1H).

Example 127.11-benzhydryl-4-hydroxy-7-methyl-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Step 1: Tert-butyl2-(1-hydroxy-2,2-diphenylethyl)-6-methylpiperidine-1-carboxylate

To a solution of tert-butyl 2-methylpiperidine-1-carboxylate (1 mL, 4.70mmol) and TMEDA (0.745 mL, 4.94 mmol) in anhydrous Et₂O (10 mL) cooledto −78° C., was added, dropwise, isopropyllithium (0.7 M in pentane)(8.06 mL, 5.64 mmol). The reaction mixture was stirred for 15 min,gradually warmed to −20° C., stirred at this temperature for 60 min andthen cooled to −72° C. 2,2-Diphenylacetaldehyde (1.251 mL, 7.05 mmol)was added to the reaction mixture which was subsequently stirred for 30min and then quenched by addition of saturated aqueous ammonium chloride(40 mL). The mixture was allowed to warm to room temperature, anddiluted with ether (100 ml) and water (50 ml). The aqueous phase wasextracted with ether (2×25 ml). The combined organic phase was driedover Na₂SO₄ and concentrated. Silica gel column chromatography(EtOAc/heptane) provided tert-butyl2-(1-hydroxy-2,2-diphenylethyl)-6-methylpiperidine-1-carboxylate (711mg) in 38% yield. MS m/z 396.4 (MH+).

Example 127.11-benzhydryl-4-hydroxy-7-methyl-7,8,9,10,10a,11-hexahydropyrido[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Prepared from tert-butyl2-(1-hydroxy-2,2-diphenylethyl)-6-methylpiperidine-1-carboxylate by themethod of Example 124A, steps 2-7A. LCMS (m/z): 416.4 (MH+), 1H NMR (500MHz, Methanol-d4) δ 7.57-7.53 (m, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.33 (d,J=8.4 Hz, 2H), 7.19-7.15 (m, 2H), 7.13 (dd, J=5.2, 2.1 Hz, 4H),5.35-5.25 (m, 1H), 4.35 (d, J=11.5 Hz, 1H), 3.84 (d, J=10.1 Hz, 1H),1.88-1.81 (m, 1H), 1.79-1.69 (m, 2H), 1.65-1.58 (m, 2H), 1.50-1.32 (m,1H), 1.06 (d, J=7.0 Hz, 3H).

Example 128.(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-5,7,8,9,9a,10-hexahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl3-methylbutanoate

To a solution of(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione(60 mg, 0.128 mmol) in DCM (3 mL) was added Hunig's base (0.054 mL,0.307 mmol) followed by 3-methylbutanoyl chloride (0.019 mL, 0.160mmol). The reaction mixture was stirred for 1 h at RT, Diluted with DCMand washed with aqueous NaHCO₃ solution. The organic layer was driedover Na₂SO₄, filtered and concentrated. The residue was dissolved inDMSO and purified by reverse phase HPLC. Product fractions werecombined, frozen and lyophilized to afford a formate salt of(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-5,7,8,9,9a,10-hexahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl3-methylbutanoate (55.5 mg, 0.099 mmol, white solid) in 76% yield.

¹H NMR (400 MHz, CD₃OD) δ ppm 7.44-7.66 (m, 3H) 7.16 (t, J=8.68 Hz, 2H)6.88-7.01 (m, 2H) 6.77-6.90 (m, 2H) 5.71 (br dd, J=9.85, 2.91 Hz, 1H)4.43-4.58 (m, 2H) 3.70-3.81 (m, 1H) 3.64 (td, J=11.14, 7.02 Hz, 1H) 2.54(d, J=6.94 Hz, 2H) 2.21 (dquin, J=13.39, 6.65, 6.65, 6.65, 6.65 Hz, 1H)1.94-2.05 (m, 1H) 1.85-1.93 (m, 1H) 1.71-1.84 (m, 1H) 1.48-1.63 (m, 1H)0.98-1.18 (m, 6H). MS m/z 508.3 (MH⁺).

TABLE 1j Additional compounds prepared by the method of Example 128.Example Mass No. Structure M + H 1H NMR 129

508.3 (400 MHz, MeOD) δ ppm 0.96- 1.18 (m, 6 H) 1.48-1.65 (m, 1 H)1.73-1.85 (m, 1 H) 1.86-1.94 (m, 1 H) 1.94-2.01 (m, 1 H) 2.20 (tt, J =13.43, 6.74 Hz, 1 H) 2.52 (d, J = 6.99 Hz, 2 H) 3.64 (td, J = 11.21,6.92 Hz, 1 H) 3.71-3.81 (m, 1 H) 4.43-4.60 (m, 2 H) 5.77 (br dd, J =9.93, 3.03 Hz, 1 H) 6.75 (br d, J = 7.92 Hz, 2 H) 6.78-6.86 (m, 1 H)7.10 (td, J = 14.44, 7.90 Hz, 2 H) 7.35-7.49 (m, 1 H) 7.35-7.49 (m, 2 H)7.54 (s, 1 H) 130

466.3 (400 MHz, DMSO-d6) δ 7.61- 7.48 (m, 2H), 7.44 (td, J = 7.9, 6.1Hz, 1H), 7.12 (tt, J = 10.2, 5.1 Hz, 2H), 6.90 (td, J = 8.9, 2.1 Hz,1H), 6.77 (d, J = 8.3 Hz, 2H), 6.69 (s, 1H), 5.77 (dd, J = 10.2, 3.5 Hz,1H), 4.64 (d, J = 10.2 Hz, 1H), 4.50 (ddd, J = 9.9, 6.1, 3.5 Hz, 1H),3.67-3.54 (m, 2H), 2.24 (s, 3H), 1.92-1.73 (m, 2H), 1.67 (d, J = 13.3Hz, 1H), 1.41-1.25 (m, 1H). 131

494.3 (400 MHz, DMSO-d6) δ 7.58 (d, J = 10.5 Hz, 1H), 7.54-7.39 (m, 3H),7.18-7.04 (m, 2H), 6.90 (t, J = 8.1 Hz, 1H), 6.79 (d, J = 7.9 Hz, 2H),5.77 (d, J = 8.9 Hz, 1H), 4.65 (d, J = 10.4 Hz, 1H), 4.50 (dt, J = 9.7,5.8 Hz, 1H), 3.59 (p, J = 12.3, 11.7 Hz, 2H), 2.79 (p, J = 7.0 Hz, 1H),1.90-1.71 (m, 2H), 1.65 (s, 1H), 1.24 (dd, J = 6.6, 3.4 Hz, 7H). 132

510.4 (500 MHz, DMSO-d6) δ 7.72- 7.63 (m, 2H), 7.55 (s, 1H), 7.26- 7.18(m, 2H), 6.97-6.84 (m, 4H), 5.69 (dd, J = 10.1, 3.5 Hz, 1H), 4.86 (p, J= 6.2 Hz, 1H), 4.61 (d, J = 10.1 Hz, 1H), 4.50 (ddd, J = 10.0, 6.2, 3.5Hz, 1H), 3.60 (dd, J = 9.9, 6.5 Hz, 2H), 1.89-1.80 (m, 1H), 1.77 (dt, J= 13.3, 6.2 Hz, 1H), 1.72-1.60 (m, 1H), 1.32 (t, J = 6.5 Hz, 7H).

Example 133.1-(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)ethylEthyl Carbonate

Added K₂CO₃ (93 mg, 0.670 mmol), KI (111 mg, 0.670 mmol) and1-chloroethyl ethyl carbonate (90 μl, 0.670 mmol) to a solution of(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione(90 mg, 0.167 mmol) in DMF (Volume: 3.3 mL) at RT. Stirred at 60° C. for4 hours, by which time the reaction was complete. The reaction mixturewas then filtered through a fritted funnel and purified by SFC(CO₂/MeOH) to provide1-(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)ethylethyl carbonate (17 mg) in 19% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 7.75(d, J=2.9 Hz, 1H), 7.68 (dd, J=8.6, 5.4 Hz, 2H), 7.28-7.13 (m, 2H), 6.90(ddt, J=27.1, 8.7, 4.6 Hz, 3H), 6.68 (dq, J=15.4, 5.2 Hz, 1H), 5.71(ddd, J=9.4, 8.0, 3.3 Hz, 1H), 4.56 (dd, J=9.5, 2.5 Hz, 1H), 4.46 (t,J=7.8 Hz, 1H), 4.09 (dqd, J=14.3, 7.1, 2.6 Hz, 2H), 3.67-3.52 (m, 2H),1.91-1.58 (m, 3H), 1.46 (d, J=5.2 Hz, 3H), 1.37 (t, J=10.1 Hz, 2H), 1.18(dt, J=11.7, 7.1 Hz, 3H). MS m/z 540.6 (M+1).

TABLE 1k Additional compounds prepared by the method of Example 133.Example Mass No. Structure M + H 1H NMR 134

541.2 (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.47 (dt, J = 10.5, 1.9 Hz,1H), 7.40-7.12 (m, 5H), 7.09- 6.95 (m, 2H), 6.44 (d, J = 10.7 Hz, 1H),5.74 (d, J = 6.6 Hz, 1H), 5.64 (d, J = 6.6 Hz, 1H), 4.74 (d, J = 10.7Hz, 1H), 4.25 (td, J = 11.5, 10.2, 6.0 Hz, 1H), 4.10 (qd, J = 7.1, 1.9Hz, 2H), 3.22 (d, J = 10.9 Hz, 1H), 2.65 (td, J = 11.2, 2.7 Hz, 1H),2.28 (td, J = 12.5, 11.3, 3.7 Hz, 1H), 1.66 (d, J = 12.2 Hz, 1H), 1.52(d, J = 11.5 Hz, 2H), 1.40- 1.25 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H) 135

556.3 (400 MHz, DMSO-d6) δ 7.65 (dd, J = 8.5, 5.3 Hz, 2H), 7.51 (s, 1H),7.21 (t, J = 8.6 Hz, 2H), 7.00- 6.83 (m, 4H), 5.74 (d, J = 6.5 Hz, 1H),5.63 (dd, J = 9.7, 3.4 Hz, 1H), 5.58 (d, J = 6.5 Hz, 1H), 4.45 (dd, J =27.0, 9.6 Hz, 2H), 4.22 (q, J = 4.7 Hz, 2H), 3.58 (dt, J = 11.9, 4.7 Hz,4H), 3.26 (s, 3H), 1.91-1.72 (m, 2H), 1.67 (dd, J = 18.0, 8.7 Hz, 1H),1.36 (p, J = 10.6 Hz, 1H) 136

540.5 (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.75 (s, 1H), 7.58 (d, J = 10.5Hz, 2H), 7.51 (d, J = 7.9 Hz, 2H), 7.47-7.38 (m, 2H), 7.09 (dt, J =14.1, 7.4 Hz, 4H), 6.85 (q, J = 8.3, 7.6 Hz, 2H), 6.77 (t, J = 7.8 Hz,3H), 6.71 (q, J = 5.2 Hz, 1H), 6.62 (q, J = 5.2 Hz, 1H), 5.78 (dt, J =8.4, 3.9 Hz, 3H), 4.68-4.57 (m, 2H), 4.48 (d, J = 5.7 Hz, 3H), 4.19-4.00 (m, 4H), 3.73-3.51 (m, 5H), 3.31 (s, 50H), 1.82 (dd, J = 11.4, 5.1Hz, 4H), 1.66 (s, 3H), 1.46 (t, J = 4.7 Hz, 5H), 1.37 (d, J = 8.9 Hz,2H), 1.19 (dt, J = 11.2, 7.1 Hz, 7H).

Example 137.(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylMethyl Carbonate

Added potassium carbonate (48.6 mg, 0.351 mmol) and iodomethyl methylcarbonate (50.6 mg, 0.234 mmol) to a solution of(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione(55 mg, 0.117 mmol) in DMF (Volume: 586 μl) at 0° C. Stirred at 0° C.for 1 hour and then RT for another hour. The reaction was filtered toremove solids and purified by SFC (CO₂/MeOH) to provide(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylmethyl carbonate (41 mg, white solid) in 68% yield. ¹H NMR (500 MHz,DMSO-d6) δ 7.71-7.62 (m, 2H), 7.52 (s, 1H), 7.27-7.14 (m, 2H), 6.98-6.85(m, 4H), 5.76 (d, J=6.5 Hz, 1H), 5.64 (dd, J=9.7, 3.4 Hz, 1H), 5.57 (d,J=6.5 Hz, 1H), 4.53 (d, J=9.7 Hz, 1H), 4.44 (ddd, J=10.0, 6.4, 3.4 Hz,1H), 3.75 (s, 3H), 3.68-3.54 (m, 2H), 1.93-1.75 (m, 2H), 1.68 (p, J=9.5,8.8 Hz, 1H), 1.45-1.33 (m, 1H). MS m/z 512.3 (M+1).

TABLE 1l Additional compounds prepared by the method of Example 137.Example Mass No. Structure M + H 1H NMR 138

526.4 (500 MHz, DMSO-d6) δ 7.71- 7.63 (m, 2H), 7.52 (s, 1H), 7.22 (t, J= 8.8 Hz, 2H), 6.98-6.86 (m, 4H), 5.74 (d, J = 6.5 Hz, 1H), 5.64 (dd, J= 9.6, 3.4 Hz, 1H), 5.58 (d, J = 6.4 Hz, 1H), 4.51 (d, J = 9.7 Hz, 1H),4.44 (ddd, J = 10.0, 6.3, 3.4 Hz, 1H), 4.17 (qq, J = 6.9, 3.5 Hz, 2H),3.67-3.54 (m, 2H), 1.91- 1.84 (m, 1H), 1.84-1.76 (m, 1H), 1.67 (p, J =9.1, 8.4 Hz, 1H), 1.39 (qd, J = 11.2, 6.7Hz, 1H), 1.25 (t, J = 7.1 Hz,3H). 139

512.2 (400 MHz, DMSO-d6) δ 7.58 (dt, J = 10.6, 2.1 Hz, 1H), 7.52 (d, J =12.4 Hz, 2H), 7.44 (td, J = 7.9, 6.2 Hz, 1H), 7.18-7.07 (m, 2H), 6.91(td, J = 8.8, 2.1 Hz, 1H), 6.82- 6.74 (m, 2H), 5.76-5.68 (m, 2H), 5.54(d, J = 6.5 Hz, 1H), 4.59 (d, J = 9.8 Hz, 1H), 4.45 (ddd, J = 10.1, 6.2,3.3 Hz, 1H), 3.74 (s, 3H), 3.68- 3.56 (m, 2H), 1.93-1.76 (m, 2H), 1.69(d, J = 8.2 Hz, 1H), 1.36 (qd, J = 11.2, 6.6 Hz, 1H). 140

526.4 (400 MHz, DMSO-d6) δ 7.58 (dt, J = 10.6, 2.2 Hz, 1H), 7.53 (s,1H), 7.52-7.40 (m, 2H), 7.18-7.07 (m, 2H), 6.91 (td, J = 7.9, 7.3, 2.2Hz, 1H), 6.82-6.74 (m, 2H), 5.76- 5.68 (m, 2H), 5.54 (d, J = 6.5 Hz,1H), 4.57 (d, J = 9.8 Hz, 1H), 4.49-4.38 (m, 1H), 4.22-4.08 (m, 2H),3.60 (dt, J = 9.2, 4.8 Hz, 2H), 1.94-1.75 (m, 2H), 1.66 (q, J = 10.2,9.6 Hz, 1H), 1.36 (dt, J = 11.6, 5.6 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H).141

540.5 (400 MHz, DMSO-d6) δ 7.57 (dt, J = 10.6, 2.1 Hz, 1H), 7.52 (s,1H), 7.51-7.39 (m, 2H), 7.13 (td, J = 7.8, 5.9 Hz, 2H), 6.95-6.87 (m,1H), 6.82-6.73 (m, 2H), 5.73 (dd, J = 9.8, 3.4 Hz, 1H), 5.68 (d, J = 6.4Hz, 1H), 5.56 (d, J = 6.4 Hz, 1H), 4.79 (p, J = 6.2 Hz, 1H), 4.55 (d, J= 9.8 Hz, 1H), 4.44 (ddd, J = 10.0, 6.4, 3.5 Hz, 1H), 3.65-3.53 (m, 2H),1.94-1.76 (m, 2H), 1.74- 1.57 (m, 1H), 1.36 (qd, J = 11.3, 6.7 Hz, 1H),1.25 (d, J = 6.2 Hz, 6H). 142

494.4 (400 MHz, DMSO-d6) δ 7.75- 7.59 (m, 2H), 7.44 (s, 1H), 7.22 (t, J= 8.8 Hz, 2H), 7.07 (qd, J = 7.7, 6.7, 3.6 Hz, 3H), 6.96-6.84 (m, 2H),5.73 (d, J = 6.5 Hz, 1H), 5.65 (dd, J = 9.8, 3.4 Hz, 1H), 5.54 (d, J =6.5 Hz, 1H), 4.45 (dd, J = 17.5, 9.8 Hz, 2H), 3.75 (s, 3H), 3.67-3.53(m, 2H), 1.94-1.75 (m, 2H), 1.68 (s, 1H), 1.51-1.32 (m, 1H). 143

538.5 (400 MHz, DMSO-d6) δ 7.58 (dd, J = 10.6, 2.4 Hz, 1H), 7.53 (s,1H), 7.51 (d, J = 8.0 Hz, 1H), 7.43 (td, J = 8.0, 6.2 Hz, 1H), 7.18-7.08(m, 2H), 6.90 (td, J = 8.8, 2.2 Hz, 1H), 6.84-6.74 (m, 2H), 5.77-5.69(m, 2H), 5.63 (d, J = 6.3 Hz, 1H), 4.57 (d, J = 9.9 Hz, 1H), 4.46- 4.35(m, 1H), 3.59 (ddd, J = 21.1, 11.8, 8.2 Hz, 2H), 1.82 (dq, J = 19.5, 6.4Hz, 2H), 1.63 (dd, J = 11.9, 6.4 Hz, 1H), 1.43-1.27 (m, 1H), 1.11 (s,9H). 144

527.1 (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.47 (d, J = 10.3 Hz, 1H),7.38-7.30 (m, 2H), 7.30-7.20 (m, 2H), 7.17 (d, J = 7.7 Hz, 1H),7.10-6.94 (m, 2H), 6.44 (d, J = 10.7 Hz, 1H), 5.76 (d, J = 6.6 Hz, 1H),5.64 (d, J = 6.6 Hz, 1H), 4.75 (d, J = 10.6 Hz, 2H), 4.27 (d, J = 11.9Hz, 2H), 3.69 (s, 3H), 2.70- 2.59 (m, 2H), 2.36-2.22 (m, 2H), 1.66 (d, J= 13.1 Hz, 1H), 1.51 (s, 2H)

Example 145.(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylL-valinate

Step 1.(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl(tert-butoxycarbonyl)-L-valinate

To a solution of(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5-dione(50 mg, 0.093 mmol) in DMF (1.8 mL) were added K₂CO₃ (51.4 mg, 0.372mmol), and KI (15.44 mg, 0.093 mmol). The mixture was cooled to 0° C.and iodomethyl (tert-butoxycarbonyl)-L-valinate (133 mg, 0.372 mmol) wasadded. The reaction was stirred at rt for 2 h and then diluted withEtOAc. The organic layer was washed with water, dried over Na₂SO₄,filtered and concentrated. Silica gel column chromatography (DCM/MeOH)provided(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl(tert-butoxycarbonyl)-L-valinate (38 mg) in 63% yield. MS m/z 653.7(MH⁺).

Step 2.(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylL-valinate

To a solution of(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl(tert-butoxycarbonyl)-L-valinate (38 mg, 0.058 mmol) in DCM (Volume: 582μl) at 0° C. was added HCl (1.0 M in Et₂O, 2.9 mL, 2.9 mmol) dropwise.The mixture was stirred for 5 h at 0° C. and maintained at 0° C.overnight. The reaction was concentrated and the residue was trituratedwith Et₂O. The solid was filtered and dried under high vacuum to providea hydrochloride salt of(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylL-valinate (15 mg) in 46% yield. ¹H NMR (400 MHz, DMSO-d6) δ 7.66 (dd,J=8.6, 5.4 Hz, 2H), 7.50 (s, 1H), 7.20 (t, J=8.7 Hz, 2H), 6.99-6.82 (m,4H), 5.77 (d, J=6.3 Hz, 1H), 5.69 (d, J=6.2 Hz, 1H), 5.64 (dd, J=9.8,3.4 Hz, 1H), 4.52 (d, J=9.7 Hz, 1H), 4.39 (t, J=9.6 Hz, 1H), 3.66-3.50(m, 2H), 3.14 (d, J=5.1 Hz, 1H), 1.92-1.72 (m, 1H), 1.60 (d, J=33.1 Hz,1H), 1.35 (dd, J=19.1, 8.7 Hz, 1H), 1.21 (d, J=4.2 Hz, 2H), 0.86 (d,J=6.8 Hz, 3H), 0.80 (t, J=7.3 Hz, 3H). MS m/z 553.4 (M+1).

Example 146.(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yldimethylcarbamate

To a solution of(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione(25 mg, 0.047 mmol) 1.5 ml of dry CH₂Cl₂ at 0° C. was addedtrimethylamine (0.1 mL), 2 drops of N, N-dimethylcarbamoyl chloride anda catalytic amount of DMAP. The mixture was stirred at rt overnight.Added another 0.1 ml Et₃N and 3 drops of N, N-dimethylcarbamoyl chloride(×3) and stirred until completion. The reaction was quenched with 5%aqueous NaHCO₃ and washed with brine. The organic layer was dried oversodium sulfate and concentrated. SFC purification (CO₂/MeOH) provided(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-5,7,8,9,9a,10-hexahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yldimethylcarbamate (12 mg) in 50% yield. ¹H NMR (400 MHz, Chloroform-d) δ7.50 (d, J=18.0 Hz, 1H), 7.34 (s, 2H), 7.12 (t, J=8.4 Hz, 2H), 6.97-6.71(m, 4H), 5.32 (s, 1H), 4.36 (d, J=58.5 Hz, 2H), 3.89-3.77 (m, 1H), 3.59(dq, J=11.8, 7.2 Hz, 1H), 3.08 (d, J=73.7 Hz, 6H), 1.89 (d, J=50.3 Hz,3H), 1.48 (s, 1H). MS m/z 495.1 (MH+).

Example 147.(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-5,7,8,9,9a,10-hexahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylethyl(methyl)carbamate

To a solution of(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione(50 mg, 0.093 mmol) in DMF (Volume: 0.5 mL) at RT was added K₂ CO₃ (77mg, 0.558 mmol), KI (61.8 mg, 0.372 mmol) and chloromethylethyl(methyl)carbamate (56.4 mg, 0.372 mmol). The mixture was stirred atrt for 4 hours. The reaction was diluted with 2.5 ml DMSO and filteredto remove solids. SFC purification (CO₂/MeOH) and silica gel columnchromatography (DCM/MeOH) provided(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-5,7,8,9,9a,10-hexahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylethyl(methyl)carbamate (9 mg) in 17% yield. 1H NMR (400 MHz,Chloroform-d) δ 7.39 (d, J=25.3 Hz, 3H), 7.11 (t, J=7.1 Hz, 2H),6.95-6.71 (m, 4H), 5.92 (s, 1H), 5.80 (d, J=3.9 Hz, 1H), 5.28 (d, J=10.2Hz, 1H), 4.38 (s, 1H), 4.25 (d, J=9.7 Hz, 1H), 3.78 (s, 1H), 3.63 (s,1H), 3.33 (s, 2H), 2.91 (d, J=14.0 Hz, 3H), 1.96 (s, 1H), 1.80 (d,J=29.9 Hz, 2H), 1.49 (s, 1H), 1.27-1.06 (m, 3H). MS m/z 539.2 (MH+).

Example 148. Methyl2-(((((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)(ethoxy)phosphoryl)oxy)acetate

To a solution of ethyl phosphorodichloridate (45 mg, 0.279 mmol) indichloromethane (1 mL) at −78° C. was added triethylamine (0.078 ml,0.558 mmol) and a solution of methyl 2-hydroxyacetate (35 mg, 0.279mmol) in dichloromethane (2 mL) dropwise. After the reaction mixture wasstirred at room temperature for 2 hours, a solution of(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione(50 mg, 0.093 mmol) and triethylamine (3 equiv) in DCM (1 mL) was added.The mixture was stirred at RT for 3 h, filtered and concentrated. SFCpurification (CO₂/MeOH) provided methyl2-(((((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)(ethoxy)phosphoryl)oxy)acetate(27 mg) in 46% yield. ¹H NMR (400 MHz, Chloroform-d) δ 7.45 (d, J=5.2Hz, 1H), 7.39-7.31 (m, 2H), 7.12 (t, J=8.5 Hz, 2H), 6.87 (q, J=7.2 Hz,2H), 6.80 (t, J=8.4 Hz, 2H), 5.33 (dt, J=10.0, 3.1 Hz, 1H), 5.01-4.90(m, 2H), 4.60-4.40 (m, 3H), 4.27 (dd, J=10.1, 2.3 Hz, 1H), 3.80 (d,J=7.1 Hz, 4H), 3.62 (dq, J=12.0, 6.9 Hz, 1H), 1.99 (d, J=13.6 Hz, 1H),1.92-1.78 (m, 2H), 1.56-1.34 (m, 4H). MS m/z 604.2 (MH+).

Example 149. Methyl2-((((((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-5,7,8,9,9a,10-hexahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methoxy)carbonyl)oxy)-2-methylpropanoate

To a solution of(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione(50 mg, 0.093 mmol) in DMF (Volume: 0.5 mL) at RT was added K₂CO₃ (77mg, 0.558 mmol), KI (61.8 mg, 0.372 mmol) and methyl2-(((chloromethoxy)carbonyl)oxy)-2-methylpropanoate (78 mg, 0.372 mmol).The mixture was stirred at rt for 4 hours. The reaction was diluted with2.5 ml DMSO and filtered to remove solids. SFC purification (CO₂/MeOH)and silica gel column chromatography (heptane/EtOAc) provided methyl2-((((((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-5,7,8,9,9a,10-hexahydro-3H-pyrrolo[1′,2′:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methoxy)carbonyl)oxy)-2-methylpropanoate(12 mg) in 20% yield. ¹FI NMR (400 MHz, Chloroform-d) δ 7.42 (s, 1H),7.37 (dd, J=8.3, 5.2 Hz, 2H), 7.12 (t, J=8.4 Hz, 2H), 6.91-6.77 (m, 4H),6.01-5.80 (m, 2H), 5.30 (dd, J=10.1, 3.2 Hz, 1H), 4.40 (d, J=4.0 Hz,1H), 4.24 (d, J=10.0 Hz, 1H), 3.76 (s, 4H), 3.61 (dq, J=11.6, 7.0 Hz,1H), 2.02-1.92 (m, 1H), 1.85 (dd, J=12.5, 6.2 Hz, 1H), 1.81-1.72 (m,1H), 1.67 (d, J=5.8 Hz, 6H), 1.53-1.45 (m, 1H). MS m/z 598.3 (MH+).

Biological Assays and Data

The activity of a compound according to the present invention can beassessed by the following in vitro and in vivo methods. Using the testassays described herein, compounds of the invention exhibit inhibitoryefficacy in accordance with Tables 2 and 3.

Influenza Virus Neuraminidase Assay (NA Assay)

For influenza NA assays, MDCK cells were plated in Phenol Red-free DMEM(Gibco) supplemented with 2 mM L-Glutamine, 1% sodium pyruvate (Cellgro,Manassas, Va.) and 0.1% BSA at cell densities of 1.8×10⁴ cells/well in384-well format. Compounds were added to the cells 2 hourspre-infection. Infections were performed at MOI 0.005 and the plateswere incubated at 37° 5% CO₂ for 48 hours. Following incubation,neuraminidase activity was evaluated with the NA assay kit(ThermoFisher, Carlsbad, Calif.). For cell toxicity measurement,CellTiter-Glo® (Promega, Madison, Wis.) was added to treated cellsaccording to manufacturer's instructions.

Influenza Virus Minigenome Assays (RNP Assay)

For influenza A virus minigenome reporter assays, 293T cells weretransfected with expression vectors encoding PB2, PB1, PA, NP proteinsand an influenza A Luciferase reporter plasmid. Cells were harvested inDulbecco's modified Eagle's medium (DMEM) minus phenol red, supplementedwith 10% heat inactivated FBS (fetal bovine serum), 1% sodium pyruvateand 1% L-glutamine (Cellgro, Manassas, Va.). The five plasmids wereco-transfected with Fugene 6 transfection reagent (Promega, Madison,Wis.) with a 1:3 ratio DNA (μg):Fugene 6 (μl), in OptiMEM® (Gibco,Carlsbad, Calif.). Transfections were performed at cell densities of1.8×10⁴ cells/well in 384-well format. Compounds were added 2 hourspost-transfection, and plates were incubated at 37° 5% CO₂ for 48 hours.Following incubation, cells were lysed and luciferase productionquantified by addition of Britelite Plus® (Perkin-Elmer, Waltham,Mass.). For cell toxicity measurement, CellTiter-Glo® (Promega, Madison,Wis.) was added to treated cells following manufacturer's instructions.

TABLE 2 Activity of Selected Compounds on multiple flu strains in the NAassay. Example NA_VIR_H1N1 NA_VIR_H3N2 NA_Hubei # EC₅₀ (μM) EC₅₀ (μM)EC₅₀ (μM)  1 0.22 1.0 0.61  2 0.085 0.55 0.27  3 0.66 1.5 0.57  4 0.0840.38 0.15  5 0.19 0.79 0.27  6 0.82 2.1 0.77  7 0.59 1.6 0.42  8 0.271.6 0.66  9 0.033 0.17 0.057 10 0.091 0.47 0.082 11 7.3 35 1.612 >50 >50 >50 13 0.35 1.1 0.34 14 0.084 0.45 0.092 15 17 30 0.88 160.11 0.44 0.067 17 0.25 1.5 0.29 18 4.4 21 9.1   19B 0.40 1.9 0.49

TABLE 3 Activity of Selected Compounds on multiple flu strains using theRNP assay Example RNP_Alaska RNP_CAL_(—) RNP_Hubei No. EC₅₀ (μM) EC₅₀(μM) EC₅₀ (μM)  1 0.42 0.13 0.20  2 0.22 0.087 0.094  3 1.4 1.1 0.79  40.16 0.27 0.10  5 0.086 0.18 0.030  6 1.3 0.56 0.51  7 1.3 0.50 0.30  80.65 2.2 0.58  9 0.051 0.045 0.026 10 0.13 0.13 0.035 11 7.3 9.3 3.5 123.5 6.9 26 13 0.32 0.47 0.18 14 0.15 0.13 0.048 15 7.0 3.5 1.2 16 0.120.059 0.038 17 0.16 0.32 0.036 18 7.8 2.6 10   19A 0.24 0.22 0.33   19B0.98 0.63 0.40 20 0.22 0.18 0.11 21 0.89 0.49 0.36 22 0.14 0.12 0.21  23A 0.28 0.25 0.29   23B 0.34 0.093 0.76 24 0.37 0.17 0.51   25A 0.350.14 0.39   25B 0.91 0.44 2.6   26A 0.075 0.026 0.16   26B 0.13 0.0580.15   27A 0.24 0.052 0.12   27B 0.082 0.063 0.14   28A 0.30 0.25 0.27  28B 0.086 0.046 0.35 29 0.11 0.093 0.18 30 0.068 0.034 0.089 31 5.31.8 8 32 0.11 0.093 0.061 33 0.10 0.097 0.046 34 0.098 0.079 0.043 350.098 0.088 0.066 36 0.29 0.12 0.033 37 0.093 0.035 0.028 38 0.024 0.300.11 39 0.091 0.074 0.049 40 0.30 0.25 0.12 41 0.073 0.088 0.043 42 0.280.31 0.10 43 0.082 0.075 0.035 44 0.15 0.16 0.10 45 0.13 0.12 0.043 460.068 0.069 0.061 47 0.093 0.068 0.032 48 0.095 0.094 0.078 49 0.0650.058 0.044 50 0.43 0.36 0.081 51 0.30 0.33 0.13 52 0.087 0.072 0.046 530.078 0.051 0.033 54 0.14 0.15 0.067 55 0.15 0.16 0.073 56 0.059 0.0480.064 57 0.092 0.11 0.080 58 0.20 0.21 0.099 59 0.18 0.18 0.069 60 0.0800.052 0.032 61 0.34 0.37 0.23 62 0.17 0.21 0.079 63 0.17 0.20 0.16 640.071 0.096 0.033 65 0.031 0.034 0.022 66 0.038 0.030 0.052 67 3.8 2.53.8 68 0.062 0.044 0.046 69 0.084 0.058 0.052 70 0.082 0.077 0.049 710.085 0.060 0.033 72 0.037 0.046 0.025 73 2.7 1.1 1.2 74 0.030 0.0340.016 75 0.24 0.28 0.11 76 0.11 0.14 0.046 77 0.038 0.049 0.030 78 0.0450.059 0.031 79 0.083 0.079 0.079 80 0.087 0.097 0.065 81 0.098 0.0990.057 82 0.092 0.15 0.061 83 0.36 0.47 0.21 84 0.093 0.069 0.036 850.054 0.047 0.041 86 0.072 0.066 0.034 87 0.058 0.052 0.061 88 0.0420.053 0.050 89 0.039 0.061 0.042 90 0.037 0.041 0.020 91 0.079 0.0900.058 92 0.040 0.031 0.036 93 0.073 0.070 0.045 94 0.52 0.50 0.12 950.13 0.12 0.055 96 0.14 0.15 0.06 97 0.15 0.18 0.074 98 0.28 0.29 0.1299 0.10 0.13 0.067 100  0.085 0.11 0.034 101  0.099 0.097 0.050 102 0.14 0.14 0.16 103  0.30 0.32 0.22 104  0.14 0.15 0.075 105  0.095 0.120.081 106  0.27 0.19 0.076 107  0.81 0.16 0.42 108  0.16 0.089 0.045109  0.12 0.11 0.045 110  0.075 0.059 0.032 111  0.073 0.050 0.072 112 0.17 0.081 0.022 113  0.052 0.030 0.032 114  0.094 0.077 0.028 115  0.120.064 0.14 116  4.7 3.6 2.9 117  0.10 0.068 0.081 118  5.5 6.2 2.6 119 0.12 0.068 0.076 120  4.6 4.5 6.2 121  0.15 0.20 0.098 122  0.88 2.10.17 123  0.34 0.27 0.45  124A 0.18 0.077 0.16  124B 0.071 <0.016 0.18 125B 0.53 0.19 0.19 126  0.47 0.23 0.25 127  0.41 0.19 0.66 128  0.0850.060 0.048 129  0.095 0.021 0.026 130  0.10 0.021 0.031 131  0.0770.066 0.025 132  0.15 0.15 0.079 133  0.097 0.070 0.068 134  0.076 0.0620.071 135  0.11 0.16 0.11 136  0.18 0.11 0.052 137  0.076 0.042 0.071138  0.11 0.18 0.11 139  0.18 0.051 0.065 140  0.11 0.096 0.050 141 0.10 0.060 0.038 142  0.14 0.17 0.061 143  0.12 0.19 0.045 144  0.0840.036 0.083 145  0.12 0.083 0.14 146  >5 >5 >5 147  >5 >5 >5 148  0.0930.098 0.13 149  0.49 0.49 0.70

1.-26. (canceled)
 27. A method of treating or preventing a viralinfection, comprising administering to a subject a therapeuticallyeffective amount of a compound of formula:

 or a pharmaceutically acceptable salt thereof, wherein: Y is a group ofthe formula

wherein the dashed line represents a bond connecting this group toFormula (A); G is H or a group selected from —C(O)R⁰, —C(O)—OR⁰,—C(R^(G))₂—O—C(O)R⁰, —C(R^(G))₂—O—C(O)—OR⁰, —P(═O)(OR⁰)₂,—(CR^(G))₂—O—P(═O)(OR⁰)₂, —C(O)—N(R⁰)₂, and —C(R^(G))₂—O—C(O)N(R⁰)₂,where each R⁰ is independently H or a group selected from C₁-C₆, alkyl,phenyl, pyridyl, C₃-C₇ cycloalkyl, and a 3-6 membered heterocyclic ringcontaining one or two heteroatoms selected from N, O and S as ringmembers; and each R⁰ that is not H is optionally substituted with one ortwo groups selected from halo, CN, —OH, amino, C₁₋₄ alkyl, COOR, phenyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy; and each R^(G) isindependently selected from H and C₁₋₄ alkyl; Z² is NR, O, S, or CH₂; Z³is CH₂, Q, —CH₂—CH₂—, -Q-CH₂—, —CH₂-Q-, —CH₂-Q-CH₂— or —CH₂—CH₂—CH₂—; Qis selected from —NR—, O, S, SO, and SO₂; R² is selected from H, halo,CN, C₁₋₄ alkyl optionally substituted with up to three groupsindependently selected from halo, CN, C₁₋₄ alkyl, —OR, C₁₋₄ haloalkoxy,—NR₂, and C₁₋₄ haloalkyl, OR, and C₁-C₄ haloalkyl; each R³ is asubstituent optionally present on any carbon atom of the ring containingZ² and Z³, and is independently selected from halo, —OR, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, oxo, CN, —NR₂, and C₁₋₄ alkyl optionally substitutedwith up to three groups independently selected from halo, CN, C₁₋₄alkyl, —OR, C₁₋₄ haloalkoxy, —NR₂, and C₁₋₄ haloalkyl; n is 0-2; Ar¹ andAr² each independently represent phenyl or a 5-6 membered heteroarylring containing 1-3 heteroatoms selected from N, O and S as ringmembers, and Ar¹ and Ar² are each independently substituted with up tothree groups selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, C₂₋₄alkyne, and CN; and Ar¹ and Ar² areoptionally linked together by a bridge of the formula —C(R^(L))₂-L- toform a tricyclic group, wherein Ar¹ and Ar² are each optionallysubstituted by up to two groups independently selected from halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkyne, andCN; R is independently at each occurrence H or C₁-C₄ alkyl optionallysubstituted with up to three groups independently selected from halo,OH, oxo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ haloalkyl; Lis selected from S, S═O, SO₂, O, NR, C(R^(L))₂ and CF₂; and and eachR^(L) is independently H or C₁₋₂ alkyl.
 28. The method of claim 27,wherein G is H.
 29. The method of claim 27, wherein G is selected from—C(O)R⁰, —C(O)—OR⁰, —C(R^(G))₂—O—C(O)R⁰, —C(R^(G))₂—O—C(O)—OR⁰,—C(O)—N(R⁰)₂, and —C(R^(G))₂—O—C(O)N(R⁰)₂, where each R⁰ isindependently H or C₁-C₄ alkyl that is optionally substituted with oneor two groups selected from halo, CN, —OH, amino, C₁₋₄ alkyl, phenyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy.
 30. The method ofclaim 29, wherein G is selected from —C(O)R⁰, —C(O)—OR⁰,—C(R^(G))₂—O—C(O)R⁰, and —C(R^(G))₂—O—C(O)—OR⁰, where each R⁰ isindependently H or a group selected from C₁-C₄ alkyl, and each R⁰ is Hor C₁-C₄ alkyl.
 31. The method of claim 30, wherein G is selected from—C(O)R⁰, —C(O)—OR⁰, —CH₂—O—C(O)R⁰, and —CH₂—O—C(O)—OR⁰, wherein each R⁰is C₁-C₄ alkyl.
 32. The method of claim 27, wherein Z² is CH₂, Z³ isCH₂, n is 0, 1 or 2, and each R³ is Me.
 33. The method of claim 27,wherein Ar¹ and Ar² are both phenyl, and Ar¹ and Ar² are independentlyoptionally substituted with one or two groups independently selectedfrom F, Cl, and C₁-C₄ alkyl.
 34. The method of claim 27, comprisingadministering to the subject one or more therapeutically activeco-agents.
 35. The method of claim 27, wherein the viral infection is anorthomyxovirus infection.
 36. The method of claim 27, wherein the viralinfection is an influenza infection.
 37. 38. A method of treating orpreventing a viral infection, comprising administering to a subject atherapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, halo,CN, COOR*, —CONR*₂, or C₁-C₆ alkyl optionally substituted with one ortwo groups selected from —OR* and —NR*₂, C₁-C₄ haloalkyl; R* isindependently at each occurrence H or C₁-C₆ alkyl optionally substitutedwith —OR or —NR₂; Z¹ is N, and Z² is C(R)₂; or Z¹ is CH, and Z² is NR,O, S, or CH₂; Z³ is CH₂, Q, —CH₂—CH₂—, -Q-CH₂—, —CH₂-Q-, —CH₂-Q-CH₂— or—CH₂—CH₂—CH₂—; Q is selected from —NR—, O, S, SO, and SO₂; R² isselected from H, halo, CN, C₁₋₄ alkyl optionally substituted with up tothree groups independently selected from halo, CN, C₁₋₄ alkyl, —OR, C₁₋₄haloalkoxy, —NR₂, and C₁₋₄ haloalkyl, OR, and C₁-C₄ haloalkyl; each R³is a substituent optionally present on any carbon atom of the ringcontaining Z² and Z³, and is independently selected from —OR, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, oxo, CN, —NR₂, and C₁₋₄ alkyl optionallysubstituted with up to three groups independently selected from halo,CN, C₁₋₄ alkyl, —OR, C₁₋₄ haloalkoxy, —NR₂, and C₁₋₄ haloalkyl; n is0-2; Ar¹ and Ar² each independently represent phenyl or a 5-6 memberedheteroaryl ring containing 1-3 heteroatoms selected from N, O and S asring members, and are each independently substituted with up to threegroups selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, C₂₋₄ alkyne, and CN; and Ar¹ and Ar² are optionally linkedtogether by a bridge of the formula —C(R^(L))₂-L- to form a tricyclicgroup, wherein Ar¹ and Ar² are each optionally substituted by up to twogroups independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkyne, and CN; R is independently ateach occurrence H or C₁-C₄ alkyl optionally substituted with up to threegroups independently selected from halo, OH, oxo, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, and C₁₋₄ haloalkyl; L is selected from S, S═O,SO₂, O, NR, C(R^(L))₂ and CF₂; and and each R^(L) is independently H orC₁₋₂ alkyl.
 39. The method of claim 38, wherein Z¹ is CH.
 40. The methodof claim 38, wherein Z² is CH₂.
 41. The method of claim 38, wherein Z³is CH₂, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—O—, or O.
 42. The method of claim41, wherein Z³ is CH₂.
 43. The method of claim 38, wherein R² is H. 44.The method of claim 38, wherein Ar¹ and Ar² are both phenyl and are eachindependently substituted with up to two groups selected from halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkyne, andCN.
 45. The method of claim 38, wherein the viral infection is anorthomyxovirus infection.
 46. The method of claim 38, wherein the viralinfection is an influenza infection.
 47. The method of claim 38,comprising administering to the subject one or more therapeuticallyactive co-agents.
 48. A method of treating or preventing a viralinfection, comprising administering to a subject a therapeuticallyeffective amount of a compound of the formula:

 or a pharmaceutically acceptable salt thereof, wherein Y represents agroup selected from

wherein Z¹ is N or CH, Z³ is CH₂, Q, —CH₂—CH₂—, -Q-CH₂—, —CH₂-Q-,—CH₂-Q-CH₂— or —CH₂—CH₂—CH₂—; Q is selected from —NR—, O, S, SO, andSO₂; each R³ is a substituent optionally present on any carbon atom ofthe ring containing Z³, and is independently selected from halo, —OR,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, oxo, CN, —NR₂, and C₁₋₄ alkyloptionally substituted with up to three groups independently selectedfrom halo, CN, C₁₋₄ alkyl, —OR, C₁₋₄ haloalkoxy, —NR₂, and CM haloalkyl;n is 0-2; each R^(y) is independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, CM alkoxy, C₁₋₄ haloalkoxy, C₂₋₄alkyne, and CN; each Ris independently at each occurrence H or C₁-C₄ alkyl optionallysubstituted with up to three groups independently selected from halo,OH, oxo, CM alkyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy, and C₁₋₄haloalkyl; andeach q is independently 0, 1 or
 2. 49. The method of claim 40, whereinZ³ is CH₂ or —CH₂—CH₂—.